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Blood, 1 January 2005, Vol. 105, No. 1, pp. 282-288.
Prepublished online as a Blood First Edition Paper on September 2, 2004; DOI 10.1182/blood-2004-07-2782.


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IMMUNOBIOLOGY

Stabilization of IFN-{gamma} mRNA by MAPK p38 in IL-12– and IL-18–stimulated human NK cells

Athanasios Mavropoulos, Gareth Sully, Andrew P. Cope, and Andrew R. Clark

From the Kennedy Institute of Rheumatology Division, Imperial College London, London, United Kingdom.

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. (Blood. 2005;105:282-288)


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