Abstract
In response to tubular injury, production, and secretion of cytokines, chemokines or extracellular matrix components by human proximal tubular epithelial cells (PTC) directly contribute to the development of tubulointerstitial inflammation and fibrosis. Here, we report a novel stimulatory and synergistic effect of oncostatin M (OSM) on proinflammatory CCL2/MCP-1 mRNA expression in human PTC. Although OSM inhibited IL-1β- and TNF-α-mediated mRNA expression of matricellular proteins TSP-1 and tenascin C (TNC), it acted synergistically with these two proinflammatory cytokines to induce CCL2 mRNA expression for up to 24 h. Stimulation of two independent human PTC lines with OSM alone led to a rapid and strong induction of this chemokine within the first hour of ligand administration, which subsequently returned toward basal levels in between 3 and 24 h and finally switched into a significant OSM-mediated 70% inhibition of basal CCL2 mRNA expression after 48 h of incubation. In contrast to OSM, which stimulated both STAT1/3 and ERK1/2 signaling, IL-1β led to a strong phosphorylation of p65 NFκB/RelA, SMAD2/3, and p38 MAPK in human PTC. Selective silencing of these signaling molecules revealed that p65 NFκB/RelA is involved in IL-1β-mediated stimulation of CCL2 mRNA, and that superinduction of CCL2 mRNA expression in the presence of both OSM and IL-1β at least partially depends on STAT3 signaling. Thus, with respect to the expression of the proinflammatory chemokine CCL2, OSM may stimulate acute inflammation via its synergistic effect with other proinflammatory cytokines early after injury.
Highlights
ONCOSTATIN M (OSM) REPRESENTS a cytokine, which has a role in physiological and pathophysiological mechanisms such as inflammation, remodeling of extracellular matrix, hematopoiesis, and modulation of cell growth and differentiation (Tanaka and Miyajima 2003; Richards 2013)
As we recently found that OSM represents a potent inhibitor of TGF-b1-induced matricellular protein expression in human proximal tubular cells (PTC) (Sarko€zi et al 2011), we studied its potential effects on TSP-1 and a 2015 The Authors
We have previously reported evidence that OSM may have a dual role in the regulation of proximal tubular epithelial cell (PTC) differentiation and phenotype (Pollack et al 2007; Sarko€zi et al 2011, 2012)
Summary
ONCOSTATIN M (OSM) REPRESENTS a cytokine, which has a role in physiological and pathophysiological mechanisms such as inflammation, remodeling of extracellular matrix, hematopoiesis, and modulation of cell growth and differentiation (Tanaka and Miyajima 2003; Richards 2013). OSM exerts distinct biological activities on a variety of cells in vivo and in vitro including the stimulation of cytokine release from cells during inflammation (Tanaka and Miyajima 2003). Inflammatory cell invasion would not occur without signals being generated and sent out from renal parenchymal cells such as tubular epithelial cells, dendritic cells, pericytes, and endothelial cells (Molitoris 2014). These renal cell types are responsible for sensing and mediating initial signals in response to injury. To transduce its signals in human, OSM binds gp130 with low affinity and as such has little to no biological activity unless a second receptor chain is recruited, either the leukemia inhibitor factor (LIF) receptor a (LIFRa) or the specific OSM receptor b chain (OSMRb) (Gearing et al 1992; Mosley et al 1996; Tanaka and Miyajima 2003)
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