Interleukin‐10 expression is autoregulated at the transcriptional level in human and murine kupffer cells

Interleukin 10 (IL‐10) is known to downregulate immune responses. The regulation of IL‐10 gene expression therefore determines the outcome of local immune reactions. We investigated time course and downregulation of IL‐10 production in primary Kupffer's cells (KC), which are known to secrete IL‐10 in response to endotoxin challenge. Human and murine KC were isolated by centrifugal elutriation and investigated for IL‐10 gene expression by a two‐step amplification procedure (reverse transcriptase–polymerase chain reaction [PCR] followed by T7‐polymerase chain reaction). We show that IL‐10 messenger ribonucleic acid (mRNA) showed a >450 fold increase in KC 2 hours after endotoxin challenge. IL‐10 protein release from KC strictly depended on de novo protein synthesis. Endotoxin mediated increase in IL‐10 gene expression was downregulated by exogenous (>350‐fold reduction of IL‐10 mRNA level), as well as endogenous IL‐10 protein, showing a negative autoregulatory feedback loop. IL‐10 receptor expression was found to be constitutive and functional in KC. Early expression of IL‐10 in KC may be of functional relevance to the outcome of immune and inflammatory reactions in the liver sinusoid. The negative autoregulation of IL‐10 expression may represent a mechanism to regain a state of functional responsiveness in the microenvironment towards new proinflammatory stimuli. In conclusion, autoregulatory downregulation of IL‐10 expression in KC may account for important regulatory steps of local immune response in the liver sinusoid.

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