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by IL-12/IL-18-Activated Macrophages Requires STAT4 Signaling and Is Inhibited by IL-41
*
Institute of Clinical Microbiology, Immunology, and Hygiene and
Department of Dermatology, University of Erlangen, Erlangen, Germany
Macrophages release IFN-
on combined stimulation with IL-12 and
IL-18, but the signaling requirements of this process and its
regulation by other cytokines are unknown. Here, we demonstrate that
STAT4 is indispensable for IL-12/IL-18-induced production of IFN- by
mouse peritoneal macrophages. Type 2 NO synthase (NOS2), which we
previously found to be a prerequisite for IL-12-induced IFN-
production in NK cells, was not required for IFN- production by
these macrophages. IL-12 alone already induced the expression of
IFN- mRNA, but nuclear translocation of STAT4, the release of
IFN- protein, and the subsequent production of NO was strictly
dependent on the simultaneous presence of IL-18. NF-
B, which
mediates IL-18 effects in T cells, was only weakly activated by IL-12
and/or IL-18 in macrophages. Known inhibitors of macrophage functions
(e.g., IL-4 and TGF-
) also suppressed macrophage IFN- production
and the subsequent production of NOS2-derived NO. The inhibitory effect
of IL-4 was paralleled by nuclear translocation of STAT6, which in
EMSAs was able to bind to the same DNA oligonucleotide as STAT4. These
results further define the production of IFN- by macrophages and
point to a diversity in the signals required for IFN- production by
various cell types.
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