Cytokine-dependent balance of mitogenic effects in primary human lung fibroblasts related to cyclic AMP signaling and phosphodiesterase 4 inhibition.
Interleukin-1beta (IL-1beta) and basic fibroblast growth factor (bFGF) are important regulators of proliferation, and their expression is increased in lungs of patients with asthma, idiopathic pulmonary fibrosis (IPF), or chronic obstructive pulmonary disease (COPD). We investigated the effect of IL-1beta and bFGF on proliferation of human lung fibroblasts and the role of COX-2, PGE(2), and cAMP in this process. Furthermore, the effect of phosphodiesterase (PDE) 3 and 4 inhibition was analyzed. In primary human lung fibroblasts low concentrations of IL-1beta (<10 pg/ml) potentiated the bFGF-induced DNA synthesis, whereas higher concentrations revealed antiproliferative effects. Higher concentrations of IL-1beta-induced COX-2 mRNA and protein associated with an increase in PGE(2) and cAMP, and all of these parameters were potentiated by bFGF. The PDE4 inhibitor piclamilast concentration-dependently reduced proliferation by a partial G1 arrest. The PDE3 inhibitor motapizone was inactive by itself but enhanced the effect of the PDE4 inhibitor. This study demonstrates that bFGF and IL-1beta act in concert to fine-tune lung fibroblast proliferation resulting in amplification or reduction. The antiproliferative effect of IL-1beta is likely attributed to the induction of COX-2, which is further potentiated by bFGF, and the subsequent generation of PGE(2) and cAMP. Inhibition of PDE4 inhibition (rather than PDE3) may diminish proliferation of human lung fibroblasts and therefore could be useful in the therapy of pathological remodeling in lung diseases.
Selige
Jens
J
Department of In-Vitro Biology 1, Nycomed GmbH, Konstanz, Germany. jens.selige@nycomed.com
Tenor
Hermann
H
Hatzelmann
Armin
A
Dunkern
Torsten
T
D001549:Benzamides / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects / Q000502:physiology; D015232:Dinoprostone / Q000819:agonists / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D018816:Genes, cdc / Q000187:drug effects; D006133:Growth Substances / Q000819:agonists*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism / Q000494:pharmacology; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D001549:Benzamides; D016207:Cytokines; D004791:Enzyme Inhibitors; D006133:Growth Substances; D053583:Interleukin-1beta; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D011724:Pyridazines; D011725:Pyridines; D016222:Fibroblast Growth Factor 2; C051270:motapizone; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517287:PDE3A protein, human; D015232:Dinoprostone; C087566:piclamilast