Intracellular interleukin 6 mediates platelet-derived growth factor-induced proliferation of nontransformed cells.

Roth, Michael; Nauck, Markus; Tamm, Michael; Perruchoud, André P.; Ziesche, Rolf; Block, Lutz H.

doi:10.1073/pnas.92.5.1312

Cited by 83 publications

(53 citation statements)

References 21 publications

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“…In turn, IL-6 has been shown to be a mitogen for human lung ®broblasts (Roth et al, 1995). However, the results of this study clearly show that OSM does not induce IL-6 production in ®broblasts, suggesting that ®broblast production of IL-6 is not directly involved is OSM-induced proliferation of lung ®broblasts.…”

Section: Discussioncontrasting

confidence: 65%

“…In other cell types OSM is a potent regulator of IL-6 production (Bernard et al, 1999;Brown et al, 1991) and in turn IL-6 has been shown to be a mitogen for human ®broblasts (Roth et al, 1995). Exposure of ®broblasts to OSM for either 24 or 48 h did not evoke the release of measurable quantities of IL-6 (data not shown).…”

Section: Effect Of Endogenous Il-6 Production On Osm-induced Prolifermentioning

confidence: 82%

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Oncostatin M stimulates proliferation, induces collagen production and inhibits apoptosis of human lung fibroblasts

Scaffidi

Mutsaers

Moodley

et al. 2002

British J Pharmacology

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6JJ1 Oncostatin M (OSM), a member of the interleukin-6 (IL-6) cytokine family, acts on a variety of cells and elicits diversi®ed biological responses, suggesting potential roles in the regulation of cell survival, di erentiation and proliferation. 2 We have examined the e ect of OSM on the regulation of human lung ®broblast proliferation, collagen production and spontaneous apoptosis. The proliferative e ects of OSM (0.5 ± 100 ng ml 71 ) were assessed using a MTS assay as well as [ 3 H]-thymidine incorporation and cell counts at 24 and 48 h. Hydroxyproline was measured as an index of procollagen production by high pressure liquid chromotography (HPLC). Apoptosis was determined by annexin staining. 3 OSM enhanced the mitotic activity of lung ®broblasts in a time and dose dependent manner. Maximum proliferation of 57% above control was observed after incubation for 48 h with 2 ng ml 71 OSM (P50.05). 4 Incubation with the mitogen activated protein kinase (MAPK) kinase inhibitor, PD98059 or the tyrosine kinase inhibitor, genestein both signi®cantly reduced the mitogenic e ect of OSM (P50.05). 5 In contrast, proliferation in response to OSM was not regulated by induction of cyclo-oxygenase and subsequent prostaglandin E 2 (PGE 2 ) release or by IL-6. 6 OSM also stimulated ®broblasts to synthesize pro-collagen by a maximum of 35% above control levels after 48 h (P50.05). 7 OSM signi®cantly inhibited the spontaneous apoptosis of ®broblasts at 24 and 48 h. 8 These results provide evidence that OSM has pro-®brotic properties and suggest that it may play a role in normal lung wound repair and ®brosis.

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Section: Discussioncontrasting

confidence: 65%

Section: Effect Of Endogenous Il-6 Production On Osm-induced Prolifermentioning

confidence: 82%

Oncostatin M stimulates proliferation, induces collagen production and inhibits apoptosis of human lung fibroblasts

Scaffidi

Mutsaers

Moodley

et al. 2002

British J Pharmacology

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“…In addition, proinflammatory cytokines and chemokines directly induce changes in vascular permeability and thrombogenicity (22,23), processes implicated in the pathogenesis of pulmonary hypertension. These cytokines were also reported to promote proliferation and migration of VSMC in vitro (18,19), and disruption of the CCR2 chemokine receptor gene decreased vascular remodeling in a model of atherosclerosis in vivo (24). Moreover, it was demonstrated that administration of an IL-1 receptor antagonist or anti-MCP-1 antibody protected against monocrotaline-induced pulmonary hypertension (25,26).…”

Section: Discussionmentioning

confidence: 97%

“…The recruitment of leukocytes is regulated by the action of cytokines and chemokines (17). These mediators also function as potent mitogens and chemoattractants for VSMC, resulting in vascular remodeling (18,19). To investigate mechanisms underlying the anti-inflammatory properties of HO-1, we examined cytokine expression in the hypoxic lung.…”

Section: Ho-1 Overexpression Inhibits Induction Of Proinflammatory Cymentioning

confidence: 99%

Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia

Minamino

Christou

Hsieh

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

352

243

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Chronic hypoxia causes pulmonary hypertension with smooth muscle cell proliferation and matrix deposition in the wall of the pulmonary arterioles. We demonstrate here that hypoxia also induces a pronounced inflammation in the lung before the structural changes of the vessel wall. The proinflammatory action of hypoxia is mediated by the induction of distinct cytokines and chemokines and is independent of tumor necrosis factor-␣ signaling. We have previously proposed a crucial role for heme oxygenase-1 (HO-1) in protecting cardiomyocytes from hypoxic stress, and potent anti-inflammatory properties of HO-1 have been reported in models of tissue injury. We thus established transgenic mice that constitutively express HO-1 in the lung and exposed them to chronic hypoxia. HO-1 transgenic mice were protected from the development of both pulmonary inflammation as well as hypertension and vessel wall hypertrophy induced by hypoxia. Significantly, the hypoxic induction of proinflammatory cytokines and chemokines was suppressed in HO-1 transgenic mice. Our findings suggest an important protective function of enzymatic products of HO-1 activity as inhibitors of hypoxia-induced vasoconstrictive and proinflammatory pathways.A cute hypoxia in the lung causes arteriolar vasoconstriction whereas prolonged hypoxia promotes proliferation and migration of vascular smooth muscle cells (VSMC) and extracellular matrix deposition in the arterial wall, a process known as vascular remodeling (1). These abnormalities are characteristic of pulmonary hypertension (2). Several clinical conditions characterized by lung inflammation have been linked to the development of chronic pulmonary hypertension (3). Interestingly, perivascular inflammatory cell infiltration as well as increased serum levels of proinflammatory cytokines, such as IL-1␤ and IL-6, have been reported in clinical cases of primary pulmonary hypertension (4, 5). However, little attention has been given up to now to the role of pulmonary inflammation in the pathogenesis of pulmonary hypertension induced by hypoxia.Heme oxygenase (HO; EC 1.14.99.3) catalyzes the oxidation of heme to carbon monoxide (CO) and biliverdin, which is then converted to bilirubin by biliverdin reductase. Three isoforms of HO have been identified: the inducible HO-1 and the constitutively expressed HO-2 and HO-3 (6, 7). Our previous in vitro data suggest that CO released by HO-1 confers protection against vasoconstriction and vascular remodeling induced by hypoxia (8 -10). More recently, Soares et al. have suggested antiinflammatory properties of HO-1 in a cardiac transplantation model, although the molecular mechanisms have not been fully elucidated (11). Our recent in vivo data using an HO-1 null mouse model suggest that HO-1 plays a central role in protecting the right ventricle from hypoxic pulmonary pressure-induced injury (12).In the present study, we established transgenic mice that overexpress HO-1 in the lung and exposed them to hypoxia to investigate the effects of HO-1 activity on the developmen...

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“…The observation that PDGF and IL-4 induced the transcriptional activation of the proin¯ammatory cytokine IL-6 and the chemokine, MCP-1 (Doucet et al, 1998;Feghali et al, 1992;Hall et al, 1989;Paquet and Pierard, 1996;Roth et al, 1992) prompted us to determine whether the common activation of Stat6 might explain these e ects. Our data showed that Stat6 was required for potent induction of IL-6 and MCP-1 by IL-4, but not exclusively by PDGF.…”

Section: Discussionmentioning

confidence: 99%

Consequences of Stat6 deletion on Sis/PDGF- and IL-4-induced proliferation and transcriptional activation in murine fibroblasts

et al. 1999

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Intracellular interleukin 6 mediates platelet-derived growth factor-induced proliferation of nontransformed cells.

Cited by 83 publications

References 21 publications

Oncostatin M stimulates proliferation, induces collagen production and inhibits apoptosis of human lung fibroblasts

Oncostatin M stimulates proliferation, induces collagen production and inhibits apoptosis of human lung fibroblasts

Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia

Consequences of Stat6 deletion on Sis/PDGF- and IL-4-induced proliferation and transcriptional activation in murine fibroblasts

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