The p38 mitogen-activated protein kinases can have opposing roles in the antigen-dependent or endotoxin-stimulated production of IL-12 and IFN-gamma.
The p38 mitogen-activated protein kinases (p38 MAPK) are activated in lymphocytes and acessory cells during innate and antigen-specific responses. We show that an inhibitor of two isoforms of p38 MAPK, SB 203580, inhibited the antigen-initiated production of IL-12, and IFN-gamma by cultures of splenic APC and naive CD4(+) T cells. Paradoxically, SB 203580 enhanced the LPS plus IFN-gamma-initiated production of IL-12 by peritoneal exudate macrophages, and the LPS-initiated of the production of both IL-12 and IFN-gamma by non-T non-B (scid) splenocytes. The enhancing effect of SB 203580 on the production of IL-12 by peritoneal exudate macrophages stimulated by LPS and IFN-gamma was dose dependent (EC(50) 0.3 microM), was only seen at lower concentrations of IFN-gamma and was due, at least in part, to a dose-dependent (IC(50) 0.3 microM) inhibition of the production of IL-10. These results indicate first, that p38 MAP kinase activity is required for the production of IL-10, as well as that of proinflammatory cytokines such as IL-12 and IFN-gamma, and, second, that the net effects of SB 203580 on the production of IL-12 and IFN-gamma can be positive or negative, depending on stimuli, cell populations, and levels of cytokines such as IFN-gamma and IL-10.
Salmon
R A
RA
The Biomedical Research Centre, University of British Columbia, Vancouver, Canada.
Guo
X
X
Teh
H S
HS
Schrader
J W
JW
D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism; D000941:Antigens / Q000276:immunology*; D019013:CD40 Antigens / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D000941:Antigens; D019013:CD40 Antigens; D007093:Imidazoles; D008070:Lipopolysaccharides; D011725:Pyridines; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580