Inhibition by IL-12 and IFN-alpha of I-309 and macrophage-derived chemokine production upon TCR triggering of human Th1 cells.
Th1 and Th2 cells, which produce distinct sets of cytokines, differentially express several chemokine receptors that may regulate their tissue-specific localization. Although the expression pattern and regulation of chemokines are likely to play a critical role in many immunopathological processes, they remain largely unknown. Here, we investigated the requirements for Th1 and Th2 cells to produce the Th2 cell-attracting chemokines thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC) and I-309. TCR triggering of Th1 and Th2 cells leads to production of MDC and I-309 (CCR4 and CCR8 ligands, respectively), whereas TARC (CCR4 ligand) is selectively produced by Th2 cells. Secretion of these chemokines appears to be independent of endogenous production of IL-4 and IFN-gamma. IL-12 and IFN-alpha, cytokines that promote the differentiation of human Th1 cells, selectively inhibit secretion and mRNA expression of MDC and I-309 by Th1 cells. Suppression of I-309 secretion results in a decreased chemotactic effect on L1.2 cells transfected with human CCR8, indicating that IL-12 and IFN-alpha may inhibit the recruitment of CCR8-expressing cells such as Th2 cells. The inhibition of Th2 cell-attracting chemokines MDC and I-309 illustrates a novel mechanism by which IL-12 and IFN-alpha could promote and maintain an ongoing Th1 response.
Iellem
A
A
Roche Milano Ricerche, Milano, Italy.
Colantonio
L
L
Bhakta
S
S
Sozzani
S
S
Mantovani
A
A
Sinigaglia
F
F
D'Ambrosio
D
D
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D054402:Chemokine CCL1; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D019742:Chemokines, CC / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism / Q000494:pharmacology*; D007371:Interferon-gamma / Q000032:analysis / Q000502:physiology; D018664:Interleukin-12 / Q000378:metabolism / Q000494:pharmacology*; D015847:Interleukin-4 / Q000032:analysis / Q000502:physiology; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D054398:Receptors, CCR4; D054401:Receptors, CCR8; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014162:Transfection
C065971:CCL1 protein, human; C106230:CCL17 protein, human; C515482:CCL22 protein, human; C515354:CCR4 protein, human; C103330:CCR8 protein, human; C502258:Ccl1 protein, mouse; C499538:Ccl17 protein, mouse; C515483:Ccl22 protein, mouse; C515355:Ccr4 protein, mouse; D054402:Chemokine CCL1; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D019742:Chemokines, CC; D016898:Interferon-alpha; D008024:Ligands; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D054398:Receptors, CCR4; D054401:Receptors, CCR8; D019707:Receptors, Chemokine; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma