Increased responsiveness of murine eosinophils to MIP-1beta (CCL4) and TCA-3 (CCL1) is mediated by their specific receptors, CCR5 and CCR8.
In the present study, we investigated the regulation of chemokine-mediated responses and receptor expression on eosinophils from mice. MIP-1alpha (CCL3) and eotaxin (CCL11) induced a significant and only partially overlapping intracellular calcium flux in antigen-elicited and peripheral blood eosinophils, and MCP-1 (CCL2), MDC (CCL22), MIP-1beta (CCL4), and TCA-3 (CCL1) did not. To demonstrate functional use of the specific receptors, we examined chemotactic responses. Peripheral blood eosinophils migrated toward MIP-1alpha (CCL3) and eotaxin (CCL11) but not MCP-1 (CCL2), MDC (CCL22), MIP-1beta (CCL4), and TCA-3 (CCL1). Antigen-elicited eosinophils migrated toward MIP-1alpha (CCL3) and eotaxin (CCL11), but also migrated in response to MIP-1beta (CCL4) and TCA-3 (CCL1), suggesting the up-regulation of additional chemokine receptors on antigen-elicited eosinophils. The up-regulation of the additional chemokine-receptor responses appeared to be in part because of cytokine activation, because TNF-alpha and/or IL-4 were able to up-regulate CCR1, -3, -5, and -8 mRNA expression in eosinophils as well as migration responses to the appropriate ligands. Using antibodies specific for CCR5 and CCR8, the chemotactic response to MIP-1beta and TCA-3, respectively, was reduced significantly. Finally, the expression of these new receptors appears to have an effect on activation and degranulation because MIP-1beta (CCL4) and TCA-3 (CCL1) induce significant levels of LTC4 from elicited eosinophils. These results suggest that eosinophils may up-regulate and use additional chemokine receptors during progression of inflammatory, allergic responses for migration and activation.
Oliveira
Sandra H P
SH
University of Michigan Medical School, Department of Pathology, Ann Arbor, MI 48109, USA.
Lira
Sergio
S
Martinez-A
Carlos
C
Wiekowski
Maria
M
Sullivan
Lee
L
Lukacs
Nicholas W
NW
D000818:Animals; D002118:Calcium / Q000097:blood; D054402:Chemokine CCL1; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC / Q000494:pharmacology*; D002630:Chemotactic Factors / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D004802:Eosinophilia / Q000209:etiology; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology*; D066298:In Vitro Techniques; D007700:Kinetics; D017997:Leukotriene C4 / Q000097:blood; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology*; D051379:Mice; D019713:Receptors, CCR5 / Q000097:blood* / Q000187:drug effects / Q000235:genetics; D054401:Receptors, CCR8; D019707:Receptors, Chemokine / Q000097:blood* / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012555:Schistosomiasis mansoni / Q000097:blood*
C103330:CCR8 protein, human; C502258:Ccl1 protein, mouse; D054402:Chemokine CCL1; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC; D002630:Chemotactic Factors; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5; D054401:Receptors, CCR8; D019707:Receptors, Chemokine; D017997:Leukotriene C4; D002118:Calcium