Oncostatin M causes VEGF release from human airway smooth muscle: synergy with IL-1β

Abstract

Vascular endothelial growth factor (VEGF), a potent angiogenesis factor, likely contributes to airway remodeling in asthma. We sought to examine the effects and mechanism of action of IL-6 family cytokines on VEGF release from human airway smooth muscle (HASM) cells. Oncostatin M (OSM), but not other IL-6 family cytokines, increased VEGF release, and IL-1beta enhanced OSM-induced VEGF release. OSM increased VEGF mRNA expression and VEGF promoter activity, whereas IL-1beta had no effect. IL-1beta did not augment the effects of OSM on VEGF promoter activity but did augment OSM-induced VEGF mRNA expression and mRNA stability. The STAT3 inhibitor piceatannol decreased both OSM-induced VEGF release and synergy between OSM and IL-1beta, without affecting responses to IL-1beta alone. Piceatannol also inhibited OSM-induced VEGF mRNA expression. In contrast, inhibitors of MAPK pathway had no effect on OSM or OSM plus IL-1beta-induced VEGF release. OSM increased type 1 IL-1 receptor (IL-1R1) mRNA expression, as measured by real-time PCR, and piceatannol attenuated this response. Consistent with the increase in IL-1R1 expression, OSM markedly augmented IL-1beta-induced VEGF, MCP-1, and IL-6 release. In summary, our data indicate OSM causes VEGF expression in HASM cells by a transcriptional mechanism involving STAT3. IL-1beta also synergizes with OSM to increase VEGF release, likely as a result of effects of IL-1beta on VEGF mRNA stability as well as effects of OSM on IL-1R1 expression. This is the first description of a role for OSM on IL-1R1 expression in any cell type. OSM may contribute to airway remodeling observed in chronic airway disease.

Monocyte‐dependent oncostatin M and TNF‐α synergize to stimulate unopposed matrix metalloproteinase‐1/3 secretion from human lung fibroblasts in tuberculosis

“…OSM is a multi-functional cytokine secreted by monocytes and T cells. It is pro-angiogenic [19], modulates growth and differentiation in normal fibroblasts [20] and some malignant cells [21], and stimulates production of acute-phase response proteins in hepatocytes [22]. OSM is secreted on LPS stimulation of mononuclear and dendritic cells, [23] both of which are important cellular effectors of a protective immune response to Mtb.…”

Asthma: where is it going?

“…Moreover, ASM cells in culture can also release growth factors such as vascular endothelial growth factor after IL-4, IL-13 and OSM stimulation, an effect strongly enhanced by the presence of OSM together with IL-4/IL-13 or with IL-1ß. These findings suggest a role for ASM cells in airway remodeling (42,43).…”

“…Compelling evidence now suggests that ASM plays an important role in regulating bronchomotor tone, in perpetuating airway inflammation, and in airway remodeling (32). Several publications have demonstrated that ASM, in addition to having contractile and proliferative properties, is also an important source of pro-inflammatory cytokines, chemokines and growth factors, as well as extracellular matrix components (19,35,36,42,43).…”

“…Several interleukin molecules have a direct role in propagating the asthmatic inflammatory process, such as IL-13, IL-4, IL-5, IL-6, and IL-11 (32,35,36,38,39,(42)(43)(44). A cycle beginning with Th2 inflammation and culminating in remodeling has been described.…”

“…ASM cells are directly involved in this cycle, perpetuating lung inflammation (40). In addition, human ASM cells in culture can also produce several compounds implicated in remodeling, including fibronectin, laminin, percelan, chondroitin, and vascular endothelial growth factor (42,43,45,46). This may be especially relevant in the presence of increased smooth muscle mass observed in asthmatic lungs (35).…”