Regulation of CD38 Expression in Human Airway Smooth Muscle Cells Role of Class I Phosphatidylinositol 3 Kinases

The ADP-ribosyl cyclase activity of CD38 generates cyclic ADP-ribose, a Ca2+-mobilizing agent. In human airway smooth muscle (HASM) cells, TNF-alpha mediates CD38 expression through mitogen-activated protein kinases and NF-kappa B and AP-1. The phosphatidylinositol-3 kinase/Akt (PI3K/Akt) pathway is involved in TNF-alpha 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-alpha 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 (p110 alpha-PIK-75 and p110 beta-TGX-221) with or without TNF-alpha. 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-alpha exposure. CD38 expression and activation of Akt, NF-kappa B, and AP-1 were determined. LY294002 and wortmannin inhibited TNF-alpha-induced Akt activation, whereas only LY294002 inhibited CD38 expression. P110 expression caused Akt activation and basal and TNF-alpha-induced CD38 expression, whereas PTEN expression attenuated Akt activation and CD38 expression. Expression levels of p110 isoforms alpha, beta, and delta were comparable in nonasthmatic and asthmatic HASM cells. Silencing of p110 alpha or -delta, but not p110 beta, resulted in comparable attenuation of TNF-alpha-induced CD38 expression in asthmatic and nonasthmatic cells. NF-kappa B 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-kappa B or AP-1 activation, and PI3K signaling may not be involved in the differential elevation of CD38 in asthmatic HASM cells.