p38a activation-mediated IFNAR1 downregulation by tumor derived factors induced neutrophil-attracting chemokines production

Tumor derived factors induced type I interferon receptor (IFNAR1) downregulation both in vivo and in vitro. IFNAR1 was shown to be phosphorylated, ubiquitinated and downregulated in response to soluble or vesicular tumor derived factors in a p38-dependent manner. Upon administration of B16F10 tumor derived factors, lungs of Ifnar1S526A knock-in mice (termed "SA"), where mutation in a phospho-acceptor site within the IFNAR1 phospho-degron renders IFNAR1 insensitive to p38-driven phosphorylation, ubiquitination and degradation, retained IFNAR1 and sustained the expression of the IFN stimulated genes. Futuremore, careful examination and validation of gene expression profiles revealed an increased expression of several chemokines known to attract neutrophils (including Cxcl1, Cxcl3 and Cxcl5) in the lungs of WT mice treated with tumor derived factors. This increase was notably less pronounced in the SA mice, suggesting that IFNAR1 downregulation by tumor derived factors induced neutrophil-attracting chemokines production. Overall design: Two biological replicates were analyzed for each of two genotypes (WT and SA)