Mycobacterium avium infection of mouse macrophages inhibits IFN-gamma Janus kinase-STAT signaling and gene induction by down-regulation of the IFN-gamma receptor

Macrophage activation is required to control the growth of intracellular pa thogens. Recent data indicate that macrophages become functionally deactiva ted during mycobacterial infection. We studied macrophage deactivation by e xamining the expression of a panel of IFN-gamma-inducible genes and activat ion of Janus Kinase (JAK)-STAT pathway in Mycobacterium avium-infected macr ophages, Reduced expression of IFN-gamma-inducible genes-MHC class II gene EP; MHC class II transactivator; IFN regulatory factor-1; and Mg21, a gene coding for a GTP-binding protein-was observed in M, avium-infected macropha ges. Decreased tyrosine phosphorylation and DNA binding activity of STAT1 i n M. avium-infected macrophages stimulated with IFN-gamma was observed. Tyr osine phosphorylation of JAK1, JAK2, and IFN-gamma R alpha was also reduced in infected cells. Northern and Western blot analyses showed that a down-r egulation of IFN-gamma R alpha- and beta-chain mRNA and protein occurred in M, avium-infected macrophages, The down-regulation of IFN-gamma R and inhi bition of STAT1 activation were time dependent and required 4 h of infectio n for down-regulation of the IFN-gamma R and 8 h for STAT1 inhibition. Thes e findings suggest that M, avium infection inhibits induction of IFN-gamma- inducible genes in mouse macrophages by down-regulating IFN-gamma R, result ing in reduced phosphorylation of IFN-gamma R alpha, JAK1, JAK2, and STAT1.