Interleukin-10 (IL-10) mediated suppression of IL-12 production in RAW 264.7 cells also involves c-rel transcription factor

Authors: Sheikh Showkat Rahim; Nooruddin Khan; Chandra Sekhar Boddupalli; Seyed E. Hasnain; Sangita Mukhopadhyay

Source: Immunology, Volume 114, Number 3, March 2005 , pp. 313-321(9)

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Abstract:

Summary

Interleukin-10 (IL-10) is known to inhibit IL-12 production in macrophages primarily at the transcriptional level with the involvement of p50 and p65 nuclear factor- kgr

B (NF-

B). We demonstrate that the c-rel transcription factor also plays a major role in IL-10-mediated IL-12 suppression. Treatment of macrophages with recombinant IL-10 inhibited nuclear c-rel levels, whereas addition of neutralizing anti-IL-10 antibody up-regulated both nuclear c-rel levels and IL-12 production by macrophages. Decreased nuclear c-rel was associated with a reduction in phosphorylation of inhibitory kappa B alpha (I kgr

) in the cytoplasm, indicating that IL-10 prevents degradation of I kgr

and the subsequent translocation of c-rel into the nucleus. Treatment with leptomycin B, a known inhibitor of c-rel at a concentration of 10 nm, when used with anti-IL-10 antibody, resulted in reduced expression of IL-12. In a complementary experiment, in vitro transient expression of p65 NF- kgr

B could not rescue the inhibitory effect of IL-10 on IL-12 production, suggesting that NF- kgr

B alone was not sufficient to restore IL-12 production during IL-10 treatment. However, over-expression of c-rel resulted in IL-12 restoration upon stimulation with lipopolysaccharide plus interferon- ggr