Hypoxia-induced interleukin-6 and interleukin-8 production is mediated by platelet-activating factor and platelet-derived growth factor in primary human lung cells.
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.
Division of Pneumology, Department of Internal Medicine, Department of Research, and Department of Thoracic Surgery, University Hospital Basel, Switzerland.
M
M
Tamm
M
M
Bihl
O
O
Eickelberg
P
P
Stulz
A P
AP
Perruchoud
M
M
Roth
D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D015687:Cell Hypoxia / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000166:cytology* / Q000276:immunology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D010972:Platelet Activating Factor / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D014158:Transcription, Genetic / Q000276:immunology
D015850:Interleukin-6; D016209:Interleukin-8; D010972:Platelet Activating Factor; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger