Changes in gene expression during inflammation are in part caused by post-transcriptional mechanisms. A transcriptome-wide screen for changes in ribosome occupancy indicated that the inflammatory cytokine IL-17 activates translation of a group of mRNAs that overlaps partially with those affected similarly by IL-1. Included are mRNAs of IκBζ and of MCPIP1, important regulators of the quality and course of immune and inflammatory responses. Evidence for increased ribosome association of these mRNAs was also obtained in LPS-activated RAW264.7 macrophages and human peripheral blood mononuclear cells. Like IL-1, IL-17 activated translation of IκBζ mRNA by counteracting the function of a translational silencing element in its 3′-UTR defined previously. Translational silencing of MCPIP1 mRNA in unstimulated cells resulted from the combined suppressive activities of its 5′-UTR, which contains upstream open reading frames, and of its 3′-UTR, which silences independently of the 5′-UTR. Only the silencing function of the 3′-UTR was counteracted by IL-17 as well as by IL-1. Translational silencing by the 3′-UTR was dependent on a putative stem-loop-forming region previously associated with rapid degradation of the mRNA. The results suggest that translational control exerted by IL-1 and IL-17 plays an important role in the coordination of an inflammatory reaction.
Background: The role of translational control mechanisms in gene expression during inflammation is incompletely understood.
Results: The proinflammatory cytokines IL-1 and IL-17 activate translation of certain mRNAs, including that of MCPIP1, a negative regulator of inflammation.
Conclusion: Translational activation of MCPIP1 contributes to changes in gene expression induced by IL-1 and IL-17.
Significance: Translational control may determine physiological and pathological consequences of inflammation.
This work was supported by Grants SFB 566/A10, SFB 566/Z2, and Ho 1116/5 from the Deutsche Forschungsgemeinschaft and by a grant from the Deutsche Krebshilfe.
