title: Synergistic induction of CCL2/MCP-1 expression driven by oncostatin M and IL-1β in human proximal tubular cells depends on STAT3 and p65 NFκB/RelA.
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.
authors.affiliation: Department of Internal Medicine IV, Nephrology and Hypertension, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Rita
authors.initials: R
authors.lastname: Sarközi
authors.affiliation: Department of Internal Medicine IV, Nephrology and Hypertension, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Corazza
authors.affiliation: Department of Internal Medicine IV, Nephrology and Hypertension, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Jan-Philipp
authors.initials: JP
authors.lastname: Osterkamp
authors.affiliation: Department of Internal Medicine IV, Nephrology and Hypertension, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Pirklbauer
authors.affiliation: Department of Internal Medicine IV, Nephrology and Hypertension, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Gert
authors.initials: G
authors.lastname: Mayer
authors.affiliation: Department of Internal Medicine IV, Nephrology and Hypertension, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Herbert
authors.initials: H
authors.lastname: Schramek
keywords: ccl2; oncostatin M; proximal tubular cell