Stabilization of IFN-gamma mRNA by MAPK p38 in IL-12- and IL-18-stimulated human NK cells.
The rapid induction of interferon-gamma (IFN-gamma) by innate cytokines such as interleukin 12 (IL-12) and IL-18 is critical for immunity against infectious pathogens. We investigated the molecular mechanisms underlying this response. IL-12 and IL-18 rapidly and synergistically induced the secretion of IFN-gamma by freshly purified human peripheral blood lymphocytes. At early time points, IFN-gamma was expressed almost exclusively by natural killer cells and in both CD56bright and CD56dim subpopulations. Mitogen-activated protein kinase p38 was activated strongly by IL-18 and weakly by IL-12 in natural killer cells but was not activated by either cytokine in T cells. The expression of IFN-gamma mRNA and protein was dose-dependently blocked by SB203580, a specific inhibitor of mitogen-activated protein kinase p38, which also caused a dramatic destabilization of IFN-gamma mRNA. The 3' untranslated region (UTR) of IFN-gamma mRNA conferred p38 responsiveness to a heterologous reporter mRNA. Therefore, the synergistic induction of IFN-gamma by IL-12 and IL-18 in natural killer cells is mediated at least in part by p38-dependent and 3' UTR-mediated stabilization of IFN-gamma mRNA.
Mavropoulos
Athanasios
A
Kennedy Institute of Rheumatology Division, Imperial College London, London, United Kingdom.
Sully
Gareth
G
Cope
Andrew P
AP
Clark
Andrew R
AR
D002478:Cells, Cultured; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D018664:Interleukin-12 / Q000494:pharmacology*; D020382:Interleukin-18 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D020382:Interleukin-18; D012333:RNA, Messenger; D018664:Interleukin-12; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases