Stem Cells http://www.peprotech.com/
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Christopherson, K.
Right arrow Articles by Hromas, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Christopherson, K., II
Right arrow Articles by Hromas, R.
Stem Cells, Vol. 19, No. 5, 388-396, September 2001
© 2001 AlphaMed Press

CONCISE REVIEW

Chemokine Regulation of Normal and Pathologic Immune Responses

Kent Christopherson, II, Robert Hromas

Indiana University Cancer Center and the Walther Oncology Institute, Indianapolis, Indiana, USA

Key Words. Chemokine • Chemotaxis • Homing • Hematopoiesis • T cell

Robert Hromas, Ph.D., Indiana University Cancer Center and the Walther Oncology Institute, R4-202, 1044 W. Walnut St., Indianapolis, Indiana 46202, USA. Telephone: 317-274-1036; Fax: 317-274-0396; e-mail: rhromas{at}iupui.edu


   ABSTRACT
Top
 Abstract
Introduction
 Chemokines and Disease
 Chemokine Regulation of the...
 Chemokine Regulation of...
 Summary
 References
 
Chemokines are small basic proteins that are the major mediators of all leukocyte migration. There are at least 46 distinct chemokines, and 19 chemokine receptors, making it easily the largest cytokine family. Chemokines can be both beneficial and harmful, by either stimulating an appropriate immune response to microbial invasion, or by mediating pathologic tissue destruction in many types of human disease. Chemokines have been implicated in the tissue destruction seen in autoimmune diseases, atherosclerosis, allograft rejection, and neoplasia. Chemokines also play essential roles in normal lymphocyte trafficking to primary and secondary lymphoid organs for antigen presentation and lymphocyte maturation. Chemokines also regulate hematopoietic stem and progenitor cell homing and proliferation. Therefore, it is likely that chemokines will become important targets for pharmacologic intervention in a wide variety of human diseases in the future.


   INTRODUCTION
Top
 Abstract
 Introduction
Chemokines and Disease
 Chemokine Regulation of the...
 Chemokine Regulation of...
 Summary
 References
 
Chemokines are a large family of cytokines that direct normal leukocyte migration and have been implicated in the regulation of leukocyte development, angiogenesis, tumor growth, and metastasis [1-4]. They perform both beneficial roles in normal host defense against infection and harmful roles in autoimmune diseases [5-7]. Chemokines have been shown to mediate inflammatory tissue destruction in a wide variety of human diseases, such as rheumatoid arthritis, myocardial infarction, and adult respiratory distress syndrome [8-14].

Chemokines are 8-12 kD heparin-binding proteins that are rich in basic amino acids and contain conserved cysteine motifs forming essential disulfide bonds between the first and thirds and the second and fourth cysteines. They are single polypeptides ranging from 70 to 100 amino acids in length and share varying degrees (20%-95%) of amino acid sequence identity. The number and spacing of the first cysteines in the amino acid sequence are used to classify chemokines into four subfamilies: C, CC, CXC, and CX3C (Table 1Go) [15-17]. If the first two cysteines are adjacent to each other, they are classified in the CC family (also known as the beta family) consisting of CCL1-27. The CXC family (also referred to as the alpha family) consisting of CXCL1-15 has a single amino acid between the initial two cysteines. Two more recently discovered chemokines (lymphotactin/XCL1-2 and fractalkine/ CX3CL1) represent the first members of the C and CX3C subfamilies. Most CXC members are located in a gene cluster on human chromosome 4 at q12-21, whereas most CC members are in a cluster on human chromosome 17 at q11-32.


View this table:
[in this window]
[in a new window]
  		Table 1. A complete list of known chemokines, their synonyms, and their target cell types for chemotaxis
 
Chemokines act through chemokine receptors (XCR1, CCR1-11, CXCR1-5, and CX3CR1) (Table 2Go), which are a subfamily of G-protein coupled seven-transmembrane receptors [16-18]. Chemokine receptors share 25%-80% amino acid sequence identity. Redundancy exists in the signaling of chemokines through chemokine receptors. Many chemokines bind to more than one chemokine receptor, and many chemokine receptors bind more than one chemokine (Table 2Go). Chemokine receptors probably signal through the Gß{gamma} subunit to activate phospholipase C and phosphatidylinositol-3 kinase [16-19]. This in turn ultimately leads to activation of the cytoskeletal regulatory kinases FAK and Pyk-2 [20, 21] that mediate chemotaxis, and in some cases activation of the MAP kinase proliferative pathway [16, 20].


View this table:
[in this window]
[in a new window]
  		Table 2. A complete list of chemokine receptors, with their synonyms, and major activity described
 

   CHEMOKINES AND DISEASE
Top
 Abstract
 Introduction
 Chemokines and Disease
Chemokine Regulation of the...
 Chemokine Regulation of...
 Summary
 References
 
Chemokines are important in a wide variety of human diseases. They play a role in autoimmune diseases, allograft rejection, infection, allergies, neoplasia, and vascular abnormalities [7, 22-24].

In autoimmune diseases, chemokines are implicated in the pathology of rheumatoid arthritis, lupus, and multiple sclerosis. Chemokines have been reported to be mediators of inflammatory tissue destruction in rheumatoid arthritis. For example, macrophage inhibitory protein (MIP)-1{alpha} and MIP-2 levels were reported to be increased in arthritic joints, and their levels were shown to increase with the severity of rheumatoid arthritis [10]. In addition, interleukin 8 (IL-8) and membrane cofactor protein-1 (MCP-1) have also been found in the synovial fluid of patients with rheumatoid arthritis [11, 22].

There are excellent animal model data that chemokines mediate multiple sclerosis (MS) [22, 25]. Mice deficient in CCR2 or MCP-1 fail to get experimental autoimmune encephalitis, the best animal model of MS. In addition, there are data from humans that indicate that chemokine levels are elevated in the cerebrospinal fluid of MS patients, and that central nervous system T-cells in MS are highly enriched for certain chemokine receptors [26].

Chemokines also play a pivotal role in allograft rejection [27]. Local graft production of non-specific inflammatory cytokines such as interferon-{gamma} stimulate the production of chemokines, which in turn attract CCR7+ T cells and dendritic cells to the graft for neo-antigen presentation, and then CXCR3+ cytotoxic T cells to mediate graft rejection. CXCR3–/– mice have markedly prolonged allograft survival.

Chemokines have been found to mediate HIV infection [28]. Reports have shown that the CC chemokines MIP-1{alpha}, MIP-1ß, and RANTES inhibit HIV-1 production in newly infected peripheral blood mononuclear cells [28]. The HIV coreceptors that function with CD4 are the chemokine receptors CCR5 and CXCR4, suggesting a mechanism for the inhibition of HIV infection by some chemokines [29-31].

Chemokines play a role in allergic reactions [5, 9, 22, 23]. Eotaxin, MCP-3, and RANTES are present at the asthma disease site in bronchial airways [5]. Through serial neutralization of chemokines using injected anti-sera, it has been shown that chemokines orchestrate the accumulation of bronchial leukocytes in airway hypersensitivity models [32].

Chemokines also mediate many vascular lesions as well, such as atherosclerosis and post-infarct reperfusion tissue destruction [2, 5, 7, 8]. In atherosclerosis, it appears that the initiating step in the origin of an atherosclerotic plaque is the induction of MCP-1 in vascular smooth muscle from flow shear stress in hypertension [33]. This stimulates the infiltration of the vascular wall by monocytes, which begin to lay down cholesterol. In addition, IL-8, MCP-1, and MIP-2 are all possible mediators of neutrophil-mediated ischemic reperfusion injury in stroke or myocardial infarction [10, 13].

Chemokines have been implicated in angiogenesis, tumor growth, and metastasis [3, 5, 15]. It is established that ELR-CXC chemokines are angiogenic (stimulate endothelial cells resulting in increased vascularization) and most non-ELR-CXC chemokines are angiostatic (inhibit ELR-CXC chemokine stimulation of endothelial cells) [3]. In addition, chemokines are implicated in tumor metastasis by their involvement in the migration of tumor cells [3]. The chemokine receptor CXCR4 is reported to be highly expressed in human malignant breast cancer cells and metastases [34]. Based on these data, it is hypothesized that SDF-1 expression, at sites of metastasis, attract metastatic cancer cells expressing the receptor CXCR4. Neutralization of the CXCR4 receptor inhibits the metastasis of breast cancer cells to lymph nodes and lung tissue [34].

Chemokines have generated interest as tumor vaccines for their chemoattractant as well as their T cell and natural killer (NK) cell stimulatory properties. The CC chemokine TCA3/I-309 can induce tumor specific and long-lasting immunity in mice that have been immunized with tumor cells expressing TCA3 [35]. Tumor cells transduced with the CC chemokine MCP-1 also stimulate a specific immune response that protects immunized rats against further tumor cell challenge [36]. The transduction of lymphotactin into cells, simultaneously with IL-2 as a T-cell-stimulatory molecule, was also effective as a tumor vaccine [37].

We and others isolated a novel subfamily of CC chemokines, comprised of Exodus-1, Exodus-2, and Exodus-3, that plays an important role in human disease (Table 1Go). They share an amino terminal DCCL (asp-cys-cys-leu) sequence that is unique among CC chemokines. Exodus-1 is also known as CCL20, Mip-3{alpha} and LARC [16, 38-40]. Exodus-2 is also known as CCL21, 6-Ckine, SLC, and TCA4 [16, 41-44]. Exodus-3 is also known as CCL19, Mip-3ß, CKß-11, and ELC [16, 39, 45].

We found that Exodus-3 (CCL19), through an NK and CD4+ cell mediated mechanism, inhibited breast cancer cell growth in the C3L5 mouse model [46]. We also found that Exodus-1, -2, and -3 (CCL19-21) inhibited chronic myelogenous leukemia progenitor proliferation [47]. This subfamily is unique in that property. Other chemokines that inhibit the normal human hematopoietic progenitor proliferation do not inhibit chronic myelogenous leukemia (CML) progenitors [47]. In addition, others also found that Exodus-2 and -3 (CCL21 and 19) also have potent immunotherapeutic activity against solid tumors, probably due to recruitment of T cells and NK cells to the target tumor [48-50].

Interestingly, a number of chemokine homologues have been found in the genomes of large DNA viruses [51]. It has been postulated that these chemokine homologues act as dominant negative inhibitors of normal chemokine function, blocking the recruitment of leukocytes to a viral infection. For example, we described the presence of two homologues of Mip-1{alpha} in the genome of Molluscum Contagiosum [52]. These chemokines inhibited the action of normal human Mip-1{alpha}. Others have found that Kaposi's sarcoma-associated herpes simplex virus (HSV) (HHV6) contains two chemokine homologues termed v-MIP I and II [53]. These two KHSV chemokines are pro-angiogenic, yet anti-chemotactic, explaining two of the major properties of Kaposi's sarcoma, the vascular and lingering nature of the lesion.


   CHEMOKINE REGULATION OF THE NORMAL IMMUNE RESPONSE
Top
 Abstract
 Introduction
 Chemokines and Disease
 Chemokine Regulation of the...
Chemokine Regulation of...
 Summary
 References
 
Chemokines also mediate important functions of the normal immune response. Perhaps their most critical role is in acquired cellular immunity. The Exodus subfamily of chemokines (CCL20, 21, 19) mentioned plays the major role in regulating T cell and dendritic cell trafficking, and antigen presentation, the core of cell-mediated immunity. In our hands Exodus-2 (CCL21) was the most potent stimulator of T cell migration of any chemokine tested [41].

By Northern blot analysis, Exodus-2 is preferentially expressed in normal human lymphoid tissues [41]. Exodus-2 is also expressed in HEL cells, an erythroleukemia cell line. Utilizing immunohistochemistry, it was determined that Exodus-2 is also expressed by the endothelial cells lining the high endothelial venule (HEV) and dendritic cells, T cells, and node stromal cells in the T-cell zone of normal human lymphoid tissue [54, 55]. Exodus-2 is also expressed in the HEV of the lymph node and facilitates the adherence and migration of naïve T cells into the secondary lymphoid tissue so that they may interact with antigen presenting cells [54-60]. Exodus-2 expression by lymph node stromal cells can attract both the naïve T cells and the dendritic cells to the T-cell zone where antigen presentation can occur [59-63].

Exodus-2 and Exodus-3 also attract dendritic cells through the CCR7 receptor present on the surface of these cells [64-66]. The role of dendritic cells in antigen-mediated immunity is to capture and process antigen in peripheral tissues. Dendritic cells then migrate to secondary lymphoid organs and present antigen to naïve T cells. The migration of CCR7-expressing dendritic cells to secondary lymphoid tissues was demonstrated to be mediated by Exodus-2 using radiolabled dendritic cells in mice [66].

The co-localization of lymphocytes and antigen-presenting cells is the primary function of secondary lymphoid organs [59-63]. Secondary lymphoid organs act as the initiation site of antigen-mediated adaptive immune responses. Since the number of T cells specific for any one antigen is low, T cells survey many secondary lymphoid organs. This permits activated dendritic cells in the secondary lymphoid organs to come into contact with many naïve T cells. This nodal T-cell survey appears to be mediated by CCR7 ligand expression [59-63, 67].

Naïve T cells, after leaving the thymus, enter lymph nodes from the blood through the HEV [59-63, 67]. Activated dendritic cells (those that display antigens derived from the infecting agents located in peripheral tissues) enter through the afferent lymphatic vessels [59-63]. In humans, Exodus-2 has been shown to induce ICAM-1 (intercellular adhesion molecule-1)/LFA-1 (leukocyte function associated molecule-1) mediated adhesion of rolling lymphocytes on the blood vessel endothelium [54, 55]. This is the mechanism by which Exodus-2 induces adherence of naïve T cells to the HEV of the lymph node.

After entering the lymph node, naïve T cells and activated dendritic cells are localized to the T-cell zone. Exodus-2 and Exodus-3 are thought to function as gradients that co-localize naïve T cells and activated dendritic cells via the CCR7 receptor expressed on their cell surface [59-63]. Exodus-2 and Exodus-3 are both expressed by stromal cells in the T-cell zone, resulting in migration toward this area. It has also been suggested that T cells and dendritic cells in the T-cell zone are also expressing Exodus-2 to further set up an appropriate concentration gradient. In a similar manner, BLC (BCA-1) is thought to attract B cells to the B-cell follicle through interactions with CXCR5 [59, 60].

The importance of Exodus-2 and Exodus-3 in T-cell trafficking has been implied by studies involving plt (paucity of lymph node T cells) mice [68-74] and CCR7-deficient mice [75]. The naturally occurring plt mouse mutation shows a loss of Exodus-2 and Exodus-3 expression. The plt mouse phenotype is currently believed to be the result of the deletion of one (designated CCl21ser) of two copies of Exodus-2 that exists in the mouse genome and the deletion of the only functional copy of Exodus-3 [71, 72]. Naïve T cells and activated dendritic cells in these mice have a defect in their ability to traffic to lymph nodes or to T-cell zones of the spleen [69-74]. The plt mouse T-cell phenotype suggests that the CCR7 ligands Exodus-2 and -3 play the major role in the regulation of naïve T-cell trafficking through secondary lymphoid organs [56-59].

Exodus-2 and Exodus-3 both bind the CC chemokine receptor CCR7 [59-63]. The CCR7 receptor has been knocked out in mice. Two phenotypic aberrations resulted from the deletion of CCR7 [75]. The first abnormality was the disordered migration of lymphocytes to secondary lymphoid organs. The second abnormality was the failure of skin dendritic cells to migrate into draining lymph nodes. These two findings support the importance of Exodus-2 and Exodus-3 in trafficking of naïve T cells and activated dendritic cells through secondary lymphoid organs. However, since Exodus-2 and Exodus-3 share the CCR7 receptor, information obtained from CCR7-deficient mice does not answer questions about the distinct function of Exodus-2 alone versus Exodus-3 with respect to the trafficking of T cells through secondary lymphoid organs.

Chemokines also are essential mediators of normal NK cell function. We and others have found that the CCR7 ligands Exodus-2 and -3 are potent stimulators of normal human activated NK cell chemotaxis [76, 77]. Significantly, we also found that both of these chemokines stimulated the proliferation of activated NK cells. Thus, in certain situations chemokines are not only mediators of migration but also of cell expansion to mount an immune response to invasion. Lymphotactin has also been found to stimulate NK cell chemotaxis [78].


   CHEMOKINE REGULATION OF HEMATOPOIESIS
Top
 Abstract
 Introduction
 Chemokines and Disease
 Chemokine Regulation of the...
 Chemokine Regulation of...
Summary
 References
 
Chemokines regulate development of hematopoietic cells in three ways. First, several members of the chemokine family inhibit proliferation of hematopoietic progenitors as measured by colony formation assays [79]. In general, with the exception mentioned above of the Exodus subfamily, this inhibition does not extend to CML progenitors [47, 80, 81]. This inhibition of normal hematopoietic progenitors can be seen both in vitro and with in vivo injection of chemokines into mice. Interestingly, this inhibition is quite synergistic, such that a combination of two chemokines in 10-fold lower doses produces the same level of inhibition as one chemokine in a 10-fold higher dose. Even one dose of chemokine in vivo can produce significant progenitor inhibition. This inhibition is protective against the cytotoxic effects on progenitors of cell cycle phase active antineoplastic agents [82, 83]. This finding led to human clinical trials with an analogue of Mip-1{alpha} (BB10010) in adjuvant chemotherapy of breast cancer in an effort to prevent chemotherapy-induced cytopenia. While there was indeed inhibition of hematopoietic progenitor proliferation prior to chemotherapy, it did not make an appreciable difference in preventing cytopenias [84].

Second, chemokines also regulate migration of hematopoietic progenitors. SDF-1 is essential for the embryonic trafficking of hematopoietic stem cells and progenitors from the fetal liver to the marrow [85, 86]. SDF-1 plays a critical role in mediating stem cell homing to the marrow after transplantation, and in stem cell mobilization for aphersis for peripheral blood stem cell transplantation [87, 88]. Other chemokines can also stimulate progenitor migration. For example, the CCR7 ligands Exodus-2 and -3 mediate chemotaxis of macrophage progenitors [89].

Third, chemokines have been suggested to participate in normal thymic T-cell development [59]. The chemokines SDF-1, Mig, IP-10/ITAC, MIP-1{alpha}, RANTES, CCR5, TECK, TARC/MDC, as well as Exodus-2 and -3 have all been suggested to be involved in lymphocyte localization and development in the thymus [59]. They do not actively attract T-cell precursors from the marrow to the thymus for further development, but localize pre-T cells to specific areas of the thymus for sequential developmental steps.


   SUMMARY
Top
 Abstract
 Introduction
 Chemokines and Disease
 Chemokine Regulation of the...
 Chemokine Regulation of...
 Summary
References
 
Chemokines are a large family of cytokines that regulate all white blood cell trafficking, from hematopoietic stem cells to mature neutrophils and lymphocytes. The amazing redundancy in this family, where receptors bind many different chemokines and many different receptors are expressed on the same cell type, allows for fine regulation of the immune response. The selective expression of distinct chemokines in distinct tissues after different stimuli produces finely tuned leukocyte infiltrates in both normal and disease states.

Chemokines play critical roles in making sure leukocytes arrive in the proper environments for appropriate maturation, and arrive at sites of infection to deal with pathologic invasion. However, when inappropriately expressed, they can mediate many autoimmune and vascular diseases. They are attractive targets for clinical intervention in these diseases. In the future, it is likely that chemokines and their receptors will be central to a number of novel pharmacologic agents.


   REFERENCES
Top
 Abstract
 Introduction
 Chemokines and Disease
 Chemokine Regulation of the...
 Chemokine Regulation of...
 Summary
 References
 

  1. Oppenheim JJ. Overview of chemokines. Adv Exp Med Biol 1993;351:183–186.[Medline]

  2. Schall TJ, Bacon KB. Chemokines, leukocyte trafficking, and inflammation. Curr Opin Immunol 1994;6:865–873.[CrossRef][Medline]

  3. Rossi D, Zlotnik A. The biology of chemokines and their receptors. Annu Rev Immunol 2000;18:217–242.[CrossRef][Medline]

  4. Kim CH, Broxmeyer HE. Chemokines: signal lamps for trafficking of T and B cells for development and effector function. J Leukoc Biol 1999;65:6–15.[Abstract]

  5. Locati M, Murphy PM. Chemokines and chemokine receptors: biology and clinical relevance in inflammation and AIDS. Annu Rev Med 1999;50:425–440.[CrossRef][Medline]

  6. Baggiolini M. Chemokines and leukocyte traffic. Nature 1998;392:565–568.[CrossRef][Medline]

  7. Feng L. Role of chemokines in inflammation and immunoregulation. Immunol Res 2000;21:203–210.[CrossRef][Medline]

  8. Furie MB, Randolph GJ. Chemokines and tissue injury. Am J Pathol 1995;146:1287–1301.[Abstract]

  9. Baggiolini M, Dahinden CA. CC chemokines in allergic inflammation. Immunol Today 1994;15:127–133.[CrossRef][Medline]

  10. Strieter RM, Standiford TJ, Huffnagle GB et al. "The good, the bad, and the ugly." The role of chemokines in models of human disease. J Immunol 1996;156:3583–3586.[Medline]

  11. Hosaka S, Akahoshi T, Wada C et al. Expression of the chemokine superfamily in rheumatoid arthritis. Clin Exp Immunol 1994;97:451–457.[Medline]

  12. Kasama T, Strieter RM, Lukacs NW et al. Interleukin-10 expression and chemokine regulation during the evolution of murine type II collagen-induced arthritis. J Clin Invest 1995;95:2868–2876.

  13. Kukielka GL, Youker KA, Michael LH et al. Role of early reperfusion in the induction of adhesion molecules and cytokines in previously ischemic myocardium. Mol Cell Biochem 1995;147:5–12.[CrossRef][Medline]

  14. Massey KD, Strieter RM, Kunkel SL et al. Cardiac myocytes release leukocyte-stimulating factors. Am J Physiol 1995;269:H980–H987.[Abstract/Free Full Text]

  15. Rollins BJ. Chemokines. Blood 1997;90:909–928.[Free Full Text]

  16. Sallusto F, Mackay CR, Lanzavecchia A. The role of chemokine receptors in primary, effector, and memory immune responses. Annu Rev Immunol 2000;18:593–620.[CrossRef][Medline]

  17. Rojo D, Suetomi K, Navarro J. Structural biology of chemokine receptors. Biol Res 1999;32:263–272.[Medline]

  18. Thelen M. Dancing to the tune of chemokines. Nat Immunol 2001;2:129–134.[CrossRef][Medline]

  19. Leopoldt D, Hanck T, Exner T et al. Gbetagamma stimulates phosphoinositide 3-kinase-gamma by direct interaction with two domains of the catalytic p110 subunit. J Biol Chem 1998;273:7024–7029.[Abstract/Free Full Text]

  20. Li Z, Jiang H, Xie W et al. Roles of PLC-beta2 and -beta3 and PI3Kgamma in chemoattractant-mediated signal transduction. Science 2000;287:1046–1049.[Abstract/Free Full Text]

  21. Wang JF, Park IW, Groopman JE. Stromal cell-derived factor-1alpha stimulates tyrosine phosphorylation of multiple focal adhesion proteins and induces migration of hematopoietic progenitor cells: roles of phosphoinositide-3 kinase and protein kinase C. Blood 2000;95:2505–2513.[Abstract/Free Full Text]

  22. Gerard C, Rollins B. Chemokines and disease. Nat Immunol 2000;2:108–115.

  23. Keane MP, Strieter RM. Chemokine signaling in inflammation. Crit Care Med 2000; 28(suppl 4):N13–N26.[CrossRef][Medline]

  24. Hjelmstrom P, Fjell J, Nakagawa T et al. Lymphoid tissue homing chemokines are expressed in chronic inflammation. Am J Pathol 2000;156:1133–1138.[Abstract/Free Full Text]

  25. Fife BT, Huffnagle GB, Kuziel WA et al. CC chemokine receptor 2 is critical for induction of experimental autoimmune encephalomyelitis. J Exp Med 2000;192:899–905.[Abstract/Free Full Text]

  26. Sorensen TL, Tani M, Jensen J et al. Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest 1999;103:807–815.[Medline]

  27. Hancock WW, Gao W, Faia KL et al. Chemokines and their receptors in allograft rejection. Curr Opin Immunol 2000;12:511–516.[CrossRef][Medline]

  28. Berger EA, Murphy PM, Farber JM. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu Rev Immunol 1999;17:657–700.[CrossRef][Medline]

  29. Feng Y, Broder CC, Kennedy PE et al. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 1996;272:872–877.[Abstract]

  30. Dragic T, Litwin V, Allaway GP et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 1996;381:667–673.[CrossRef][Medline]

  31. Alkhatib G, Combadiere C, Broder CC et al. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 1996;272:1955–1958.[Abstract]

  32. Gonzalo JA, Lloyd CM, Wen D et al. The coordinated action of CC chemokines in the lung orchestrates allergic inflammation and airway hyperresponsiveness. J Exp Med 1998;188:157–167.[Abstract/Free Full Text]

  33. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999;340:115–126.[Free Full Text]

  34. Muller A, Homey B, Soto H et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001;410:50–56.[CrossRef][Medline]

  35. Laning J, Kawasaki H, Tanaka E et al. Inhibition of in vivo tumor growth by the beta chemokine, TCA3. J Immunol 1994;153:4625–4635.[Abstract]

  36. Manome Y, Wen PY, Hershowitz A et al. Monocyte chemoattractant protein-1 (MCP-1) gene transduction: an effective tumor vaccine strategy for non-intracranial tumors. Cancer Immunol Immunother 1995;41:227–235.[Medline]

  37. Dilloo D, Bacon K, Holden W et al. Combined chemokine and cytokine gene transfer enhances antitumor immunity. Nat Med 1996;2:1090–1095.[CrossRef][Medline]

  38. Hromas R, Gray PW, Chantry D et al. Cloning and characterization of Exodus, a novel beta-chemokine. Blood. 1997;89:3315–3322.[Abstract/Free Full Text]

  39. Rossi DL, Vicari AP, Franz-Bacon K et al. Identification through bioinformatics of two new macrophage proinflammatory human chemokines: MIP-3alpha and MIP-3beta. J Immunol 1997;158:1033–1036.[Abstract]

  40. Hieshima K, Imai T, Opdenakker G et al. Molecular cloning of a novel human CC chemokine liver and activation-regulated chemokine (LARC) expressed in liver. Chemotactic activity for lymphocytes and gene localization on chromosome 2. J Biol Chem 1997;272:5846–5853.[Abstract/Free Full Text]

  41. Hromas R, Kim CH, Klemsz M et al. Isolation and characterization of Exodus-2, a novel C-C chemokine with a unique 37-amino acid carboxyl-terminal extension. J Immunol 1997;159:2554–2558.[Abstract]

  42. Hedrick JA, Zlotnik A. Identification and characterization of a novel beta chemokine containing six conserved cysteines. J Immunol 1997;159:1589–1593.[Abstract]

  43. Nagira M, Imai T, Hieshima K et al. Molecular cloning of a novel human CC chemokine secondary lymphoid-tissue chemokine that is a potent chemoattractant for lymphocytes and mapped to chromosome 9p13. J Biol Chem 1997;272:19518–19524.[Abstract/Free Full Text]

  44. Tanabe S, Lu Z, Luo Y et al. Identification of a new mouse beta-chemokine, thymus-derived chemotactic agent 4, with activity on T lymphocytes and mesangial cells. J Immunol 1997;159:5671–5679.[Abstract]

  45. Yoshida R, Imai T, Hieshima K et al. Molecular cloning of a novel human CC chemokine EBI1-ligand chemokine that is a specific functional ligand for EBI1, CCR7. J Biol Chem 1997;272:13803–13809.[Abstract/Free Full Text]

  46. Braun SE, Chen K, Foster RG et al. The CC chemokine CK beta-11/MIP-3 beta/ELC/Exodus 3 mediates tumor rejection of murine breast cancer cells through NK cells. J Immunol 2000;164:4025–4031.[Abstract/Free Full Text]

  47. Hromas R, Cripe L, Hangoc G et al. The Exodus subfamily of cc chemokines inhibits the proliferation of chronic myelogenous leukemia progenitors. Blood 2000;95:1506–1508.[Abstract/Free Full Text]

  48. Sharma S, Stolina M, Luo J et al. Secondary lymphoid tissue chemokine mediates T cell-dependent anti-tumor responses in vivo. J Immunol 2000;164:4558–4563.[Abstract/Free Full Text]

  49. Vicari AP, Ait-Yahia S, Chemin K et al. Antitumor effects of the mouse chemokine 6Ckine/SLC through angiostatic and immunological mechanisms. J Immunol 2000;165:1992–2000.[Abstract/Free Full Text]

  50. Nomura T, Hasegawa H. Chemokines and anti-cancer immunotherapy: anti-tumor effect of EBI1-ligand chemokine (ELC) and secondary lymphoid tissue chemokine (SLC). Anticancer Res 2000;20:4073–4080.[Medline]

  51. Murphy PM. Viral exploitation and subversion of the immune system through chemokine mimicry. Nat Immunol 2001;2:116–122.[CrossRef][Medline]

  52. Krathwohl MD, Hromas R, Brown DR et al. Functional characterization of the C-C chemokine-like molecules encoded by molluscum contagiosum virus types 1 and 2. Proc Natl Acad Sci USA 1997;94:9875–9880.[Abstract/Free Full Text]

  53. Gallo RC. The enigmas of Kaposi's Sarcoma. Science 1998;282:1837–1839.[Free Full Text]

  54. Campbell JJ, Hedrick J, Zlotnik A et al. Chemokines and the arrest of lymphocytes rolling under flow conditions. Science 1998;279:381–384.[Abstract/Free Full Text]

  55. Gunn MD, Tangemann K, Tam C et al. A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes. Proc Natl Acad Sci USA 1998;95:258–263.[Abstract/Free Full Text]

  56. Tangemann K, Gunn MD, Giblin P et al. A high endothelial cell-derived chemokine induces rapid, efficient, and subset-selective arrest of rolling T lymphocytes on a reconstituted endothelial substrate. J Immunol 1998;161:6330–6337.[Abstract/Free Full Text]

  57. Campbell JJ, Bowman EP, Murphy K et al. 6-C-kine (SLC), a lymphocyte adhesion-triggering chemokine expressed by high endothelium, is an agonist for the MIP-3beta receptor CCR7. J Cell Biol 1998;141:1053–1059.[Abstract/Free Full Text]

  58. Stein JV, Rot A, Luo Y et al. The CC chemokine thymus-derived chemotactic agent 4 (TCA-4, secondary lymphoid tissue chemokine, 6Ckine, exodus-2) triggers lymphocyte function-associated antigen 1-mediated arrest of rolling T lymphocytes in peripheral lymph node high endothelial venules. J Exp Med 2000;191:61–76.[Abstract/Free Full Text]

  59. Hedrick JA, Zlotnik A. Chemokines and chemokine receptors in T-cell development. Chem Immunol 1999;72:57–68.[Medline]

  60. Campbell JJ, Butcher EC. Chemokines in tissue-specific and microenvironment-specific lymphocyte homing. Curr Opin Immunol 2000;12:336–341.[CrossRef][Medline]

  61. Cyster JG. Chemokines and cell migration in secondary lymphoid organs. Science 1999;286:2098–2102.[Abstract/Free Full Text]

  62. Cyster JG. Leukocyte migration: scent of the T zone. Curr Biol 2000;10:R30–R33.[CrossRef][Medline]

  63. von Andrian UH, Mackay CR. T-cell function and migration. Two sides of the same coin. N Engl J Med 2000;343:1020–1034.[Free Full Text]

  64. Kellermann SA, Hudak S, Oldham ER et al. The CC chemokine receptor-7 ligands 6Ckine and macrophage inflammatory protein-3 beta are potent chemoattractants for in vitro- and in vivo-derived dendritic cells. J Immunol 1999;162:3859–3864.[Abstract/Free Full Text]

  65. Iwasaki A, Kelsall BL. Localization of distinct Peyer's patch dendritic cell subsets and their recruitment by chemokines macrophage inflammatory protein (MIP)-3alpha, MIP-3beta, and secondary lymphoid organ chemokine. J Exp Med 2000;191:1381–1394.[Abstract/Free Full Text]

  66. Saeki H, Moore AM, Brown MJ et al. Cutting edge: secondary lymphoid-tissue chemokine (SLC) and CC chemokine receptor 7 (CCR7) participate in the emigration pathway of mature dendritic cells from the skin to regional lymph nodes. J Immunol 1999;162:2472–2475.[Abstract/Free Full Text]

  67. Ansel KM, Ngo VN, Hyman PL et al. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 2000;406:309–314.[CrossRef][Medline]

  68. Nakano H, Tamura T, Yoshimoto T et al. Genetic defect in T lymphocyte-specific homing into peripheral lymph nodes. Eur J Immunol 1997;27:215–221.[Medline]

  69. Nakano H, Mori S, Yonekawa H et al. A novel mutant gene involved in T-lymphocyte-specific homing into peripheral lymphoid organs on mouse chromosome 4. Blood 1998;91:2886–2895.[Abstract/Free Full Text]

  70. Gunn MD, Kyuwa S, Tam C et al. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J Exp Med 1999;189:451–460.[Abstract/Free Full Text]

  71. Vassileva G, Soto H, Zlotnik A et al. The reduced expression of 6Ckine in the plt mouse results from the deletion of one of two 6Ckine genes. J Exp Med 1999;190:1183–1188.[Abstract/Free Full Text]

  72. Luther SA, Tang HL, Hyman PL et al. Coexpression of the chemokines ELC and SLC by T zone stromal cells and deletion of the ELC gene in the plt/plt mouse. Proc Natl Acad Sci USA 2000;97:12694–12699.[Abstract/Free Full Text]

  73. Nakano H, Gunn MD. Gene duplications at the chemokine locus on mouse chromosome 4: multiple strain-specific haplotypes and the deletion of secondary lymphoid-organ chemokine and EBI-1 ligand chemokine genes in the plt mutation. J Immunol 2001;166:361–369.[Abstract/Free Full Text]

  74. Mori S, Nakano H, Aritomi K et al. Mice lacking expression of the chemokines CCL21-Ser and CCL19 (plt Mice) demonstrate delayed but enhanced T Cell immune responses. J Exp Med 2001;193:207–218.[Abstract/Free Full Text]

  75. Forster R, Schubel A, Breitfeld D et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 1999;99:23–33.[CrossRef][Medline]

  76. Taub DD, Sayers TJ, Carter CR et al. Alpha and beta chemokines induce NK cell migration and enhance NK-mediated cytolysis. J Immunol 1995;155:3877–3888.[Abstract]

  77. Robertson MJ, Williams BT, Christopherson 2nd K et al. Regulation of human natural killer cell migration and proliferation by the exodus subfamily of CC chemokines. Cell Immunol 2000;199:8–14.[CrossRef][Medline]

  78. Hedrick JA, Saylor V, Figueroa D et al. Lymphotactin is produced by NK cells and attracts both NK cells and T cells in vivo. J Immunol 1997;158:1533–1540.[Abstract]

  79. Youn BS, Mantel C, Broxmeyer HE. Chemokines, chemokine receptors and hematopoiesis. Immunol Rev 2000;177:150–174.[CrossRef][Medline]

  80. Eaves AC, Barnett MJ, Ponchio L et al. Differences between normal and CML stem cells: potential targets for clinical exploitation. STEM CELLS 1998;16(suppl 1):77–83.

  81. Eaves CJ, Cashman JD, Wolpe SD et al. Unresponsiveness of primitive chronic myeloid leukemia cells to macrophage inflammatory protein 1alpha, an inhibitor of primitive normal hematopoietic cells. Proc Natl Acad Sci USA 1993;90:12015–12019.[Abstract/Free Full Text]

  82. Dunlop DJ, Wright EG, Lorimore S et al. Demonstration of stem cell inhibition and myeloprotective effects of SCI/rhMIP1 alpha in vivo. Blood 1992;79:2221–2225.[Abstract/Free Full Text]

  83. Lord BI, Dexter TM, Clements JM et al. Macrophage-inflammatory protein protects multipotent hematopoietic cells from the cytotoxic effects of hydroxyurea in vivo. Blood 1992;79:2605–2609.[Abstract/Free Full Text]

  84. Broxmeyer HE, Orazi A, Hague NL et al. Myeloid progenitor cell proliferation and mobilization effects of BB10010, a genetically engineered variant of human macrophage inflammatory protein-1alpha, in a phase I clinical trial in patients with relapsed/refractory breast cancer. Blood Cells Mol Dis 1998;24:14–30.[CrossRef][Medline]

  85. Nagasawa T, Hirota S, Tachibana K et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 1996;382:635–638.[CrossRef][Medline]

  86. Ma Q, Jones D, Borghesani PR et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci USA 1998;95:9448–9453.[Abstract/Free Full Text]

  87. Hidalgo A, Sanz-Rodriguez F, Rodriguez-Fernandez JL et al. Chemokine stromal cell-derived factor-1alpha modulates VLA-4 integrin-dependent adhesion to fibronectin and VCAM-1 on bone marrow hematopoietic progenitor cells. Exp Hematol 2001;29:345–355.[CrossRef][Medline]

  88. Jo DY, Rafii S, Hamada T et al. Chemotaxis of primitive hematopoietic cells in response to stromal cell-derived factor-1. J Clin Invest 2000;105:101–111.[Medline]

  89. Kim CH, Broxmeyer HE. SLC/exodus2/6Ckine/TCA4 induces chemotaxis of hematopoietic progenitor cells: differential activity of ligands of CCR7, CXCR3, or CXCR4 in chemotaxis vs. suppression of progenitor proliferation. J Leukoc Biol 1999;66:455–461.[Abstract]

Received May 17, 2001; accepted for publication June 19, 2001.



This article has been cited by other articles:


Home page
 Am. J. Pathol.Home page
G. E. Garcia, L. D. Truong, P. Li, P. Zhang, R. J. Johnson, C. B. Wilson, and L. Feng
Inhibition of CXCL16 Attenuates Inflammatory and Progressive Phases of Anti-Glomerular Basement Membrane Antibody-Associated Glomerulonephritis
Am. J. Pathol., May 1, 2007; 170(5): 1485 - 1496.
[Abstract] [Full Text] [PDF]

Home page
 J Mol EndocrinolHome page
F. Barbieri, A. Bajetto, C. Porcile, A. Pattarozzi, G. Schettini, and T. Florio
Role of stromal cell-derived factor 1 (SDF1/CXCL12) in regulating anterior pituitary function
J. Mol. Endocrinol., March 1, 2007; 38(3): 383 - 389.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
V. Bitko, A. Musiyenko, and S. Barik
Viral Infection of the Lungs through the Eye
J. Virol., January 15, 2007; 81(2): 783 - 790.
[Abstract] [Full Text] [PDF]

Home page
 Int ImmunolHome page
N. Iijima, Y. Yanagawa, J. M. Clingan, and K. Onoe
CCR7-mediated c-Jun N-terminal kinase activation regulates cell migration in mature dendritic cells
Int. Immunol., September 1, 2005; 17(9): 1201 - 1212.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
V. Wittamer, B. Bondue, A. Guillabert, G. Vassart, M. Parmentier, and D. Communi
Neutrophil-Mediated Maturation of Chemerin: A Link between Innate and Adaptive Immunity
J. Immunol., July 1, 2005; 175(1): 487 - 493.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
D. P. Widney, Y. Hu, A. K. Foreman-Wykert, K. C. Bui, T. T. Nguyen, B. Lu, C. Gerard, J. F. Miller, and J. B. Smith
CXCR3 and Its Ligands Participate in the Host Response to Bordetella bronchiseptica Infection of the Mouse Respiratory Tract but Are Not Required for Clearance of Bacteria from the Lung
Infect. Immun., January 1, 2005; 73(1): 485 - 493.
[Abstract] [Full Text] [PDF]

Home page
 Ann. N. Y. Acad. Sci.Home page
D. L. EIZIRIK, B. KUTLU, J. RASSCHAERT, M. DARVILLE, and A. K. CARDOZO
Use of Microarray Analysis to Unveil Transcription Factor and Gene Networks Contributing to {beta} Cell Dysfunction and Apoptosis
Ann. N.Y. Acad. Sci., November 1, 2003; 1005(1): 55 - 74.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. Rev.Home page
S. WERNER and R. GROSE
Regulation of Wound Healing by Growth Factors and Cytokines
Physiol Rev, July 1, 2003; 83(3): 835 - 870.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
S. Barbero, R. Bonavia, A. Bajetto, C. Porcile, P. Pirani, J. L. Ravetti, G. L. Zona, R. Spaziante, T. Florio, and G. Schettini
Stromal Cell-derived Factor 1{alpha} Stimulates Human Glioblastoma Cell Growth through the Activation of Both Extracellular Signal-regulated Kinases 1/2 and Akt
Cancer Res., April 15, 2003; 63(8): 1969 - 1974.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. Z. Fernandis, R. P. Cherla, R. D. Chernock, and R. K. Ganju
CXCR4/CCR5 Down-modulation and Chemotaxis Are Regulated by the Proteasome Pathway
J. Biol. Chem., May 10, 2002; 277(20): 18111 - 18117.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
M. J. Robertson
Role of chemokines in the biology of natural killer cells
J. Leukoc. Biol., February 1, 2002; 71(2): 173 - 183.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Christopherson, K.
Right arrow Articles by Hromas, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Christopherson, K., II
Right arrow Articles by Hromas, R.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
STEM CELLS THE ONCOLOGIST CME ALPHAMED PRESS JOURNALS
http://www.stemcellsportal.com/