New mechanisms of action and signaling by TNF-α

Excerpt

TNF-α is a key pathogenic factor in inflammatory arthritis. Rapid and transient signaling and functional responses of cells to TNF-α, such as activation of NF-γB and MAPKs, are well known. These signaling mechanisms are widely assumed to be functional in cells chronically exposed to TNF-α and to mediate the pathogenic effects of TNF-α in chronic inflammation. We investigated the responses of primary macrophages to TNF-α over the course of several days and compared patterns of signaling and gene expression to RA synovial macrophages. The acute inflammatory response to TNF-α subsided after several hours and was followed by an IFN response characterized by sustained expression of STAT1 and downstream target genes. TNF-α-mediated induction of an IFN response was mediated by IFN-β and was sensitive to inhibition by Jak inhibitors. Concomitantly TNF-α induced a state of macrophage resistance to the homeostatic cytokines IL-10 and IL-27. Microarray analysis demonstrated that sustained TNF-α signaling induced expression of novel genes not appreciated to be 'TNF-inducible', but are highly expressed in RA synovial macrophages. Induction of an IFN response and abrogation of homeostatic cytokine signaling was also observed in RA synovial macrophages and likely contributes to the pathogenic actions of TNF-α during arthritis. …