Oncostatin M Receptor-β Signaling Limits Monocytic Cell Recruitment in Acute Inflammation

Abstract

Although the IL-6-related cytokine oncostatin M (OSM) affects processes associated with disease progression, the specific function of OSM in the face of an inflammatory challenge remains unclear. In this report, a peritoneal model of acute inflammation was used to define the influence of OSM on chemokine-mediated leukocyte recruitment. When compared with wild-type and IL-6-deficient mice, peritoneal inflammation in oncostatin M receptor-β-deficient (OSMR-KO) mice resulted in enhanced monocytic cell trafficking. In contrast to IL-6-deficient mice, OSMR-KO mice displayed no difference in neutrophil and lymphocyte migration. Subsequent in vitro studies using human peritoneal mesothelial cells and an in vivo appraisal of inflammatory chemokine expression after peritoneal inflammation identified OSM as a prominent regulator of CCL5 expression. Specifically, OSM inhibited IL-1β-mediated NF-κB activity and CCL5 expression in human mesothelial cells. This was substantiated in vivo where peritoneal inflammation in OSMR-KO mice resulted in a temporal increase in both CCL5 secretion and NF-κB activation. These findings suggest that IL-6 and OSM individually affect the profile of leukocyte trafficking, and they point to a hitherto unidentified interplay between OSM signaling and the inflammatory activation of NF-κB.

Oncostatin M and interleukin-31: Cytokines, receptors, signal transduction and physiology

“…Loss of Reg3b expression correlated with decreased the number of macrophages in the ischemic heart, accompanied by increased ventricular dilatation. Interestingly, infiltration of myeloid cells to the infarction zone was significantly decreased in Osmr À/À mice [117], which is in contrast to a study by Hams et al in which increased monocyte trafficking was observed in Osmr À/À mice in an animal model of acute peritoneal inflammation [118]. Differences in induction of inflammation (sterile vs. bacterial) or the site of inflammation might contribute to these differences, which needs to be investigated further.…”

Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling

“…A similar pattern of expression is also seen with OSMRβ, yet this gp130-like protein is also widely expressed in stromal compartments, such as fibroblasts and mesothelial and endothelial cells (44,53,54). IL-11Rα is largely confined to nonhematopoietic stromal cells, while IL-27Rα is restricted to lymphocytes, monocytes, and osteoclasts (14,55).…”

“…Other gp130-related cytokines may, however, govern defined aspects of pathology, as is illustrated by the role of IL-11 and OSM in bone turnover (42). Indeed, OSMRβ-KO mice exhibit impaired hepatocyte proliferation (43) and altered monocytic cell trafficking (44), while OSM deficiency is associated with thymic hyperplasia and glomerulonephritis (45). Despite these apparent roles for other gp130-related cytokines in autoimmunity, therapies that target IL-6 or its receptor remain the most developed strategies.…”

The Enigmatic Cytokine Oncostatin M and Roles in Disease

“…Chimeric OSMR β knockout mice engrafted with wild-type bone marrow showed reduced erythrocytic and megakaryocytic progenitors, indicating that the OSMR β was required for the hematopoietic microenvironment. A number of other studies have shown defects of OSMR β -deficient mice in acute inflammation [84], liver regeneration [85], thymic hypoplasia [81], and net metabolism of bone [86] and fat [87]. …”