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IL‐10 modulates cytokine gene transcription by protein synthesis‐independent and dependent mechanisms in lipopolysaccharide‐treated neutrophils

We have recently reported that the ability of IL‐10 to rapidly exert its anti‐inflammatory effects on human neutrophils is dependent upon exposure of these cells to LPS for at least 3–4 h. Here, we demonstrate that, in neutrophils "preconditioned" by LPS, IL‐10 primarily targets the transcription of TNF‐α, CXCL8 and IL‐1ra genes, as revealed by primary transcript real‐time RT‐PCR. We also show that IL‐10‐induced transcriptional repression of TNF‐α and CXCL8 genes consists of two distinct phases: an early one, occurring rapidly and in a protein synthesis‐independent manner, followed by a second phase, more delayed and dependent on protein synthesis. Interestingly, the protein synthesis dependence of the latter phase coincides with a reduced ability of IL‐10 to induce STAT3 tyrosine phosphorylation. Importantly, inhibition of IL‐10‐induced STAT3 activation and IL‐10‐suppressive action by a prolonged exposure to cycloheximide (CHX) was observed to occur also in human monocytes and was caused by a defective IL‐10‐mediated activation of Jak1 and Tyk2 kinases. Taken together, our findings suggest that CHX interferes with the IL‐10‐mediated intracellular signaling pathway by interrupting events upstream of STAT3 activation. These data question the concept of the requirement of an IL‐10‐induced mediator as the unique mechanism to execute IL‐10 anti‐inflammatory program.