Interleukin‐10‐induced gene expression and suppressive function are selectively modulated by the PI3K‐Akt‐GSK3 pathway

Interleukin‐10 (IL‐10) is an immunosuppressive cytokine that inhibits inflammatory gene expression. Phosphatidylinositol 3‐kinase (PI3K) ‐mediated signalling regulates inflammatory responses and can induce IL‐10 production, but a role for PI3K signalling in cellular responses to IL‐10 is not known. In this study we investigated the involvement of the PI3K‐Akt‐GSK3 signalling pathway in IL‐10‐induced gene expression and IL‐10‐mediated suppression of Toll‐like receptor‐induced gene expression in primary human macrophages. A combination of loss and gain of function approaches using kinase inhibitors, expression of constitutively active Akt, and RNA interference in primary human macrophages showed that expression of a subset of IL‐10‐inducible genes was dependent on PI3K‐Akt signalling. The effects of PI3K‐Akt signalling on IL‐10 responses were mediated at least in part by glycogen synthase kinase 3 (GSK3). In accordance with a functional role for PI3K pathways in contributing to the suppressive actions of IL‐10, PI3K signalling augmented IL‐10‐mediated inhibition of lipopolysaccharide‐induced IL‐1, IL‐8 and cyclo‐oxygenase‐2 expression. The PI3K signalling selectively modulated IL‐10 responses, as it was not required for inhibition of tumour necrosis factor expression or for induction of certain IL‐10‐inducible genes such as SOCS3. These findings identify a new mechanism by which PI3K‐mediated signalling can suppress inflammation by regulating IL‐10‐mediated gene induction and anti‐inflammatory function.

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