Regulation and phenotype of an innate Th1 cell: role of cytokines and the p38 kinase pathway.
We have explored the phenotype and regulation of Th1 cell activation by the cytokines IL-12 and IL-18. We demonstrate that these two cytokines selectively induce IFN-gamma in a differentiated Th1 cell population through the previously described p38 mitogen-activated protein (MAP) kinase pathway. Using a highly selective p38 MAP kinase inhibitor, we demonstrate that it is possible to block IFN-gamma induction from activated, differentiated Th1 cells via p38 MAP kinase without disrupting the activation and differentiation of naive T cells or the proliferation of naive or differentiated T cells. In addition, IL-12 and IL-18 provide an Ag and IL-2-independent survival signal to this uniquely differentiated Th1 cell population. We hypothesize that this Ag-independent survival of Th1 cells may participate in an innate inflammatory loop with monocytes at the sites of chronic inflammation. In addition, p38 MAP kinase inhibition of this cytokine-regulated pathway may be a unique mechanism to inhibit chronic inflammation without disruption of Ag-driven activation and function of naive T cells.
Yu
Jeffrey J
JJ
Department of Arthritis and Inflammation Pharmacology, Pharmacia Corporation, St. Louis, MO 63198, USA.
Tripp
Catherine S
CS
Russell
John H
JH
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D017209:Apoptosis / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D002908:Chronic Disease; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018984:Epitopes, T-Lymphocyte / Q000502:physiology; D007113:Immunity, Innate; D016130:Immunophenotyping; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000502:physiology; D020382:Interleukin-18 / Q000502:physiology; D037181:Lectins, C-Type; D020935:MAP Kinase Signaling System / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D018417:Th1 Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D016572:Cyclosporine; D016207:Cytokines; D004791:Enzyme Inhibitors; D018984:Epitopes, T-Lymphocyte; D007371:Interferon-gamma; D018664:Interleukin-12; D020382:Interleukin-18; D037181:Lectins, C-Type; D020928:Mitogen-Activated Protein Kinases; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D048051:p38 Mitogen-Activated Protein Kinases; D000099192:CD69 Antigens