Oncostatin M receptor signalling regulates monocytic cell trafficking during acute inflammation [Abstract]
Although the interleukin (IL)-6 related cytokine oncostatin-M (OSM) affects a variety of inflammatory events associated with disease progression, the function of OSM in the face of an inflammatory challenge remains unclear. In this current report a peritoneal model of acute inflammation has been used to define the influence of OSM on chemokine-mediated leukocyte recruitment. When compared to wild type mice (WT) the induction of peritoneal inflammation in oncostatin-M receptor-β deficient mice (OSMR-KO) resulted in enhanced monocytic cell trafficking. No difference in neutrophil and lymphocyte migration was however noted suggesting that OSM control of leukocyte recruitment is functionally distinct from that of IL-6. Subsequent in vitro studies using human peritoneal mesothelial cells and an in vivo appraisal of inflammatory chemokine expression following peritoneal inflammation inferred that OSM regulation of CCL5 might account for the observed difference in monocytic cell trafficking. Indeed through comparative analysis of inflammatory events triggered in OSMR-KO and IL-6KO mice it is evident that certain chemokines commonly regulated in vitro by both IL-6 and OSM are preferentially regulated in vivo by one prevailing factor. In this respect, it is evident that IL-6 acts as a more prominent in vivo regulator of CCL2 expression than OSM. In contrast, OSM was found to uniquely inhibit the IL-1β driven expression of CCL5. This was substantiated in vivo where induction of peritoneal inflammation in OSMR-KO mice resulted in significantly raised CCL5 levels, as compared to WT and IL-6KO mice. No difference in CCL3 and CCL4 was however noted. Mechanistically, these studies inferred a hitherto unidentified interplay between OSM-mediated STAT signaling and NF-κB activation. In this respect, EMSA analysis of nuclear extracts from peritoneal membranes isolated during course of the inflammatory response showed that OSMR-KO mice display an enhanced profile of NF-κB activation as compared to WT mice. These findings suggest that activation of gp130 by IL-6 and OSM trigger distinct inflammatory responses to affect individual aspects of leukocyte trafficking. The outcome of such a response may ultimately rely on a defined ability to modulate NF-κB signaling.