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Nicotine‐induced up‐regulation of Wingless/Int signaling in human alveolar interstitial fibroblasts (AIFs)
Author(s) -
Cerny Laura,
Sakurai Reiko,
Wang Ying,
Guo Pinzheng,
Torday John S,
Rehan Virender K
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.928.10
Subject(s) - wnt signaling pathway , calphostin c , nicotine , microbiology and biotechnology , signal transduction , chemistry , protein kinase c , calphostin , transdifferentiation , biology , medicine , stem cell
Nicotine induces AIF‐to‐myofibroblast (MYF) transdifferentiation. Since these phenotypes are determined by Peroxisome Proliferator‐Activated Receptor (PPAR)γ and Wnt signaling, respectively, we hypothesized that nicotine down‐regulates PPARγ signaling and up‐regulates Wnt signaling. And since nicotine activates PKC, we hypothesized nicotine up‐regulates Wnt signaling via PKC activation. WI38 cells were treated with nicotine 10 −6 M for 30 min or 24 hours +/− 30 minute pretreatment with calphostin C (10 −7 ), a pan‐PKC inhibitor. Cell lysates were analyzed by Western blotting for activation of 1) PKC (p‐PKC) and 2) Wnt signaling (p‐GSK‐3β, β‐catenin, LEF‐1, and fibronectin); and 3) down‐regulation of PPARγ. We also examined activation of nicotinic acetylcholine receptors (nAChR)‐α3 and –α7, up‐stream regulators of Wnt signaling. Following 30 min of nicotine stimulation, nAChR‐α3 and –α7 were up‐regulated, accompanied by activation of PKC and Wnt signaling and significant changes in expression of down‐stream targets of Wnt signaling at 24h. All changes were blocked by calphostin C, indicating the central involvement of PKC in nicotine‐induced activation of Wnt signaling, and hence AIF‐to‐MYF transdifferentiation. Therefore PKC signaling plays a central role in nicotine‐induced activation of Wnt signaling, providing novel preventive/therapeutic targets. Funding‐NIH HL75405 & TRDRP 14RT‐0013.