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Am. J. Respir. Cell Mol. Biol., Volume 19, Number 4, October, 1998 653-661

Hypoxia-Induced Interleukin-6 and Interleukin-8 Production Is Mediated by Platelet-Activating Factor and Platelet-Derived Growth Factor in Primary Human Lung Cells

Michael Tamm, Michel Bihl, Oliver Eickelberg, Peter Stulz, André P. Perruchoud, and Michael Roth

Division of Pneumology, Department of Internal Medicine, Department of Research, and Department of Thoracic Surgery, University Hospital Basel, Basel, Switzerland

Hypoxia has been shown to induce the expression of different growth factors, cytokines, and proinflammatory mediators, including platelet-derived growth factor (PDGF), interleukin-6 (IL-6), interleukin-8 (IL-8), and platelet-activating factor (PAF) in animal models. PAF and PDGF are thought to play important roles in vascular remodeling and have been shown to induce expression of IL-6 and IL-8 genes under normoxic conditions. We hypothesize that de novo synthesis of IL-6, IL-8, and cell proliferation is enhanced in human pulmonary cells under hypoxic cell culture conditions. We further assumed an important role of PAF and/or PDGF in hypoxia-induced cell activation. Using cultures of primary human pulmonary fibroblasts and pulmonary vascular smooth muscle cells (VSMC) we show that hypoxia (3% O2) induced transcription and translation of IL-6 (4- to 5-fold) and IL-8 (5- to 6-fold) in both cell types. Hypoxia-induced expression of IL-6 was suppressed by 50% to 60% in the presence of the PAF antagonist WEB2170, or neutralizing anti-PDGF antibodies. In addition, we demonstrate that hypoxia induces a threefold increase of cell proliferation of fibroblasts and a twofold increase of VSMC proliferation. Similar to the effect on IL-6 and IL-8 synthesis, WEB2170 or neutralizing anti-PDGF antibodies downregulated hypoxia-induced proliferation of fibroblasts and VSMC by 50%. Our data show that PAF and PDGF are important mediators for hypoxia-induced cell activation and cytokine release in the human lung. We therefore hypothesize that IL-6 and IL-8 contribute to the progression of lung diseases associated with hypoxia, and that both proinflammatory factors, PAF and PDGF, are involved in hypoxia-dependent expression of IL-6 and IL-8 in human pulmonary fibroblasts and VSMC.




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Copyright © 1998 American Thoracic Society. 		  2009/2010 ATS Fellows Career Development Awards