Hypoxia modulates the effects of transforming growth factor-beta isoforms on matrix-formation by primary human lung fibroblasts.
Chronic hypoxia is implicated in lung fibrosis, which is characterized by enhanced deposition of extracellular matrix (ECM) molecules. Transforming growth factor-beta (TGF-beta) plays a key role in fibroblast homeostasis and is involved in disease states characterized by excessive fibrosis, such as pulmonary fibrosis. In this study, we investigated if hypoxia modulates the effects of TGF-beta on the expression of gelatinases: matrix metalloproteinase (MMP)-2 and MMP-9, interstitial collagenases: MMP-1 and MMP-13, tissue inhibitors of MMP (TIMP), collagen type I and interleukin-6 (IL-6). Primary human lung fibroblasts, established from tissue biopsies, were cultivated under normoxia or hypoxia in the presence of TGF-beta1, TGF-beta2 or TGF-beta3. Gelatinases were assessed by gelatin zymography and collagenases, TIMP, collagen type I and IL-6 by ELISA. Under normoxia fibroblasts secreted MMP-2, collagenases, TIMP, collagen type I and IL-6. TGF-betas significantly decreased MMP-1 and increased TIMP-1, IL-6 and collagen type I. Hypoxia significantly enhanced MMP-2, and collagenases. Compared to normoxia, the combination of TGF-beta and hypoxia reduced MMP-1, and further amplified the level of TIMP, IL-6, and collagen type I. Thus, in human lung fibroblasts hypoxia significantly increases the TGF-betas-induced secretion of collagen type I and may be associated to the accumulation of ECM observed in lung fibrosis.
Papakonstantinou
Eleni
E
Department of Pharmacology, School of Medicine, Aristotle University, 54124 Thessaloniki, Greece.
Aletras
Alexios J
AJ
Roth
Michael
M
Tamm
Michael
M
Karakiulakis
George
G
D024042:Collagen Type I / Q000096:biosynthesis; D017364:Collagenases / Q000378:metabolism; D005109:Extracellular Matrix / Q000201:enzymology / Q000378:metabolism*; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000201:enzymology / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020033:Protein Isoforms / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D024042:Collagen Type I; D015850:Interleukin-6; D020033:Protein Isoforms; D011498:Protein Precursors; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1