Title: Regulation of CD38 expression in human airway smooth muscle cells: role of class I phosphatidylinositol 3 kinases.
Authors: Jude, Joseph A; Tirumurugaan, Krishnaswamy G; Kang, Bit Na; Panettieri, Reynold A; Walseth, Timothy F; Kannan, Mathur S
Published In Am J Respir Cell Mol Biol, (2012 Oct)
Abstract: The ADP-ribosyl cyclase activity of CD38 generates cyclic ADP-ribose, a Ca(2+)-mobilizing agent. In human airway smooth muscle (HASM) cells, TNF-α mediates CD38 expression through mitogen-activated protein kinases and NF-κB and AP-1. The phosphatidylinositol-3 kinase/Akt (PI3K/Akt) pathway is involved in TNF-α signaling and contributes to airway hyperresponsiveness and airway remodeling. We hypothesized that PI3Ks mediate CD38 expression and are involved in the differential induction of CD38 by TNF-α in asthmatic HASM cells. HASM cells were treated with pan-PI3K inhibitors (LY294002 or wortmannin) or class I-selective (GDC0941) or isoform-selective PI3K inhibitors (p110α-PIK-75 and p110β-TGX-221) with or without TNF-α. HASM cells were transfected with a catalytically active form of PI3K or phosphatase and tensin homolog (PTEN) or nontargeting or p110 isoform-targeting siRNAs before TNF-α exposure. CD38 expression and activation of Akt, NF-κB, and AP-1 were determined. LY294002 and wortmannin inhibited TNF-α-induced Akt activation, whereas only LY294002 inhibited CD38 expression. P110 expression caused Akt activation and basal and TNF-α-induced CD38 expression, whereas PTEN expression attenuated Akt activation and CD38 expression. Expression levels of p110 isoforms α, β, and δ were comparable in nonasthmatic and asthmatic HASM cells. Silencing of p110α or -δ, but not p110β, resulted in comparable attenuation of TNF-α-induced CD38 expression in asthmatic and nonasthmatic cells. NF-κB and AP-1 activation were unaltered by the PI3K inhibitors. In HASM cells, regulation of CD38 expression occurs by specific class I PI3K isoforms, independent of NF-κB or AP-1 activation, and PI3K signaling may not be involved in the differential elevation of CD38 in asthmatic HASM cells.
PubMed ID: 22556157
MeSH Terms: ADP-ribosyl Cyclase 1/genetics; ADP-ribosyl Cyclase 1/metabolism*; Asthma/enzymology; Asthma/metabolism; Asthma/pathology; Cells, Cultured; Chromones/pharmacology; Class Ia Phosphatidylinositol 3-Kinase/antagonists & inhibitors; Class Ia Phosphatidylinositol 3-Kinase/genetics; Class Ia Phosphatidylinositol 3-Kinase/metabolism*; Enzyme Activation; Gene Expression Regulation*; Gene Knockdown Techniques; Humans; Isoenzymes/antagonists & inhibitors; Isoenzymes/genetics; Isoenzymes/metabolism; Membrane Glycoproteins/genetics; Membrane Glycoproteins/metabolism*; Morpholines/pharmacology; Myocytes, Smooth Muscle/enzymology*; Myocytes, Smooth Muscle/metabolism; NF-kappa B/metabolism; PTEN Phosphohydrolase/metabolism; Primary Cell Culture; Proto-Oncogene Proteins c-akt; Pyrimidinones/pharmacology; RNA Interference; Respiratory System/pathology*; Signal Transduction; Transcription Factor AP-1/metabolism; Tumor Necrosis Factor-alpha/physiology