Mechanism for nicotine-induced up-regulation of Wnt signaling in human alveolar interstitial fibroblasts.
Nicotine exposure alters normal homeostatic pulmonary epithelial-mesenchymal paracrine signaling pathways, resulting in alveolar interstitial fibroblast (AIF)-to-myofibroblast (MYF) transdifferentiation. Since the AIF versus MYF phenotype is determined by the expression of peroxisome proliferator-activated receptor γ (PPARγ) and Wingless/Int (Wnt) signaling, respectively, the authors hypothesized that nicotine-induced AIF-to-MYF transdifferentiation is characterized by the down-regulation of PPARγ, and the up-regulation of the Wnt signaling pathway. As nicotine is known to activate protein kinase C (PKC) signaling, the authors also hypothesized that in AIFs, nicotine-induced up-regulation of Wnt signaling might be due to PKC activation. Embryonic human lung fibroblasts (WI38 cells) were treated with nicotine (1 × 10(-6) M) for either 30 minutes or 24 hours, with or without 30-minute pretreatment with calphostin C (1 × 10(-7) M), a pan-PKC inhibitor. Then the authors examined the activation of PKC (p-PKC) and Wnt signaling (p-GSK-3β, β-catenin, LEF-1, and fibronectin). Furthermore, activation of nicotinic acetylcholine receptor (nAChR)-α3 and -α7 and whether a PPARγ agonist, rosiglitazone (RGZ), blocks nicotine-mediated Wnt activation were examined. Following nicotine stimulation, there was clear evidence for nAChR-α3 and -α7 up-regulation, accompanied by the activation of PKC and Wnt signaling, which was further accompanied by significant changes in the expression of the downstream targets of Wnt signaling at 24 hours. Nicotine-mediated Wnt activation was almost completely blocked by pretreatment with either calphostin C or RGZ, indicating the central involvement of PKC activation and Wnt/PPARγ interaction in nicotine-induced up-regulation of Wnt signaling, and hence AIF-to-MYF transdifferentiation, providing novel preventive/therapeutic targets for nicotine-induced lung injury.
Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, Torrance, California, USA.
Reiko
R
Sakurai
Laura M
LM
Cerny
John S
JS
Torday
Virender K
VK
Rehan
D001483:Base Sequence; D002460:Cell Line; D054338:Cell Transdifferentiation / Q000187:drug effects / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009281:Naphthalenes / Q000494:pharmacology; D009538:Nicotine / Q000633:toxicity*; D047495:PPAR gamma / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D011978:Receptors, Nicotinic / Q000378:metabolism; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D045162:Thiazolidinediones / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D051153:Wnt Proteins / Q000378:metabolism*; D064569:alpha7 Nicotinic Acetylcholine Receptor; D051176:beta Catenin / Q000378:metabolism
C495270:CTNNB1 protein, human; C579167:Chrna7 protein, human; D017931:DNA Primers; D009281:Naphthalenes; D047495:PPAR gamma; D011978:Receptors, Nicotinic; D045162:Thiazolidinediones; D051153:Wnt Proteins; D064569:alpha7 Nicotinic Acetylcholine Receptor; D051176:beta Catenin; D000077154:Rosiglitazone; D009538:Nicotine; D011493:Protein Kinase C; C058819:calphostin C