Fragile X‐related protein FXR1 controls post‐transcriptional suppression of lipopolysaccharide‐induced tumour necrosis factor‐α production by transforming growth factor‐β1

Tumour necrosis factor‐α (TNF‐α) is a key mediator of inflammation in host defence against infection and in autoimmune disease. Its production is controlled post‐transcriptionally by multiple RNA‐binding proteins that interact with the TNF‐α AU‐rich element and regulate its expression; one of these is Fragile X mental retardation‐related protein 1 (FXR1). The anti‐inflammatory cytokine transforming growth factor‐β1 (TGF‐β1), which is involved in the homeostatic regulation of TNF‐α, causes post‐transcriptional suppression of lipopolysaccharide (LPS)‐induced TNF‐α production. We report here that this depends on FXR1. Using RAW 264.7 cells and bone marrow‐derived macrophages (BMDMϕ) stimulated with LPS and TGF‐β1, we show that TGF‐β1 inhibits TNF‐α protein secretion, whereas TNF‐α mRNA expression remains unchanged. This response is recapitulated by the 3′‐UTR of TNF‐α, which is known to bind FXR1. TGF‐β1 induces FXR1 with a pattern of expression distinct from that of tristetraprolin, T‐cell intracellular antigen 1, or human antigen R. When FXR1 is knocked down, TGF‐β1 is no longer able to inhibit LPS‐induced TNF‐α protein production, and overexpression of FXR1 suppresses LPS‐induced TNF‐α protein production. Targeting the p38 mitogen‐activated protein kinase pathway of LPS‐treated cells with small molecule inhibitors can induce FXR1 protein and mRNA expression. In summary, TGF‐β1 opposes LPS‐induced stabilization of TNF‐α mRNA and reduces the amount of TNF‐α protein, through induction of expression of the mRNA‐binding protein FXR1.