Interleukin-10 targets p38 MAPK to modulate ARE-dependent TNF mRNA translation and limit intestinal pathology

Interleukin-10 (IL-10) is a key inhibitory signal of inflammatory responses that regulates the production of potentially pathogenic cytokines like tum or necrosis factor (TNF). We show here that the development of chronic inte stinal inflammation in IL-10-deficient mice requires the function of TNF, i ndicating that the IL-10/TNF axis regulates mucosal immunity. We further sh ow that IL-10 targets the 3 ' AU-rich elements (ARE) of TNF mRNA to inhibit its translation. Moreover, IL-10 does not alter TNF mRNA stability, and it s action does not require the presence of the stability-regulating ARE bind ing factor tristetraprolin, indicating a differential assembly of stability and translation determinants on the TNF ARE. Inhibition of TNF translation by IL-10 is exerted mainly by inhibition of the activating p38/MAPK-activa ted protein kinase-2 pathway. These results demonstrate a physiologically s ignificant cross-talk between the IL-10 receptor and the stress-activated p rotein kinase modules targeting TNF mRNA translation. This crosstalk is nec essary for optimal TNF production and for the maintenance of immune homeost asis in the gut.