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Blood, 15 August 2004, Vol. 104, No. 4, pp. 911-912. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Jones, D. Search for Related Content PubMed Articles by Jones, D. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CHEMOKINES Comment on Flaishon et al, page 933 CCR2: holding B cells back Dan Jones, M. D. ANDERSON CANCER CENTER In this issue, Flaishon et al describe a novel role for the chemokine receptor CCR2 and its ligand CCL2/JE in inhibiting the chemotactic response of immature B cells to the chemokine CXCL12/SDF-1. Although best known for their chemoattractant properties, chemokines also modulate the cellular response to other chemokines. Flaishon and colleagues describe a role for the C-C chemokine receptor 2 (CCR2) and its ligand CCL2/JE in inhibiting the chemotactic response of immature B cells to the chemokine CXCL12/stromal cell–derived factor 1 (SDF-1). They show that CCR2-deficient immature mouse B cells have increased migratory capacity to CXCL12/SDF-1 in vitro and that pretreatment of CCR2-positive immature B cells with CCL2/JE decreases their responsiveness to CXCL12/SDF-1. Injected CCR2-deficient immature B cells also accumulated at higher levels in the lymph nodes of mice compared with wild-type B cells. The precise mechanism of this heterologous desensitization mediated by CCR2 was not identified, but signaling cross talk was suggested. In particular, they showed that the expression level of the CXCL12/SDF-1 receptor CXCR4 and the calcium flux following CXCL12/SDF-1 binding were unaffected by CCL2/JE pretreatment, whereas there was decreased CXCL12/SDF-1–induced phosphoactivation of extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK). Inhibition of CXCR4 signaling by CCR2 ligands has also been seen in other cell types.1 Besides its expression in immature B cells, CCR2 is also expressed in a subset of mature B-cell neoplasms.2 It has previously been shown that CCR5 binding can also induce heterologous desensitization to CXCL12/SDF-1 in immature human B cells,3 a finding that was also observed in T cells. It will be of interest to discover if the mechanisms of CXCR4 signaling inhibition are similar between these 2 receptors and whether they are operative in human B-cell tumors, nearly all of which respond to CXCL12/SDF-1. JE inhibits SDF-1–induced migration of 70Z/3 cells because of inhibition of ERK phosphorylation. See the complete figure in the article beginning on page 933.   Heterologous desensitization in immature B cells provides further demonstration that chemokines can compete with each other in complex ways to influence leukocyte localization. The most obvious competitive mechanism is the differential temporal and spatial expression gradients for each chemokine. Given that most leukocytes express several chemokine receptors and that several chemokines bind to most receptors with varying affinities, modeling these interactions becomes dauntingly complex. The frequent autocrine expression of chemokines by the migrating cell itself may also dampen responses to exogenous chemokines. Feedback from downstream effects of chemokines can also negatively regulate chemotactic response as with T cells, where chemokines promote adhesion and cellular activation, which subsequently affects loss of chemotactic response to some but not other chemokines.4 Finally, the production of agonist and antagonist chemokines by ubiquitous human herpes viruses provides additional opportunities for chemokine competition in pathologic states. For most leukocytes, chemokine competition, including through heterologous desensitization, likely plays a dominant role in ultimately determining localization patterns. References Lee B, Doranz BJ, Rana S, et al. Influence of the CCR2-V64I polymorphism on human immunodeficiency virus type 1 coreceptor activity and on chemokine receptor function of CCR2b, CCR3, CCR5, and CXCR4. J Virol. 1998;72: 7450-7458.[Abstract/Free Full Text] Trentin L, Cabrelle A, Facco M, et al. Homeostatic chemokines drive migration of malignant B cells in patients with non-Hodgkin's lymphomas. Blood. Prepublished on March 4, 2004, as DOI 10.1182/blood-2003-09-3103. (Now available as Blood. 2004;104: XXX-XXX) Honczarenko M, Le Y, Glodek AM, et al. CCR5-binding chemokines modulate CXCL12 (SDF-1)-induced responses of progenitor B cells in human bone marrow through heterologous desensitization of the CXCR4 chemokine receptor. Blood. 2002;100: 2321-2329.[Abstract/Free Full Text] Bromley SK, Peterson DA, Gunn MD, Dustin ML. Cutting edge: hierarchy of chemokine receptor and TCR signals regulating T cell migration and proliferation. J Immunol. 2000;165: 15-19.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Expression of the chemokine receptor CCR2 on immature B cells negatively regulates their cytoskeletal rearrangement and migration Liat Flaishon, Shirly Becker-Herman, Gili Hart, Yoram Levo, William A. Kuziel, and Idit Shachar Blood 2004 104: 933-941. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Jones, D. Search for Related Content PubMed Articles by Jones, D. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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