TNF-α induced CD38 expression in human airway smooth muscle cells: role of MAP kinases and transcription factors NF-κB and AP-1

Abstract

In human airway smooth muscle (HASM) cells, the expression of CD38, which synthesizes the calcium-mobilizing molecule cyclic ADP-ribose, is augmented by TNF-alpha, a cytokine implicated in asthma. We determined the role of mitogen-activated protein kinase (MAPK) in the activation of NF-kappaB and AP-1 in the regulation of CD38 expression in HASM cells. In HASM cells exposed to TNF-alpha (40 ng/ml), the inhibitors of extracellular signal-regulated kinase (ERK), p38, or c-Jun NH(2)-terminal kinase (JNK) decreased CD38 expression and ADP-ribosyl cyclase activity. Transfection of HASM cells with a dominant negative MEK decreased while a wild-type ERK increased TNF-alpha-induced CD38 expression. Electrophoretic mobility shift assays (EMSAs) were performed using nuclear proteins and consensus sequences to detect the effect of the MAPKs on NF-kappaB and AP-1 activation. EMSAs confirmed the role of p38 and JNK in mediating NF-kappaB and AP-1 activation. Transfection of a dominant negative c-Jun decreased TNF-alpha-induced CD38 expression indicating involvement of AP-1. Stability of TNF-alpha-induced CD38 transcripts were determined in the presence of MAPK inhibitors after arresting the transcription with actinomycin D. Transcript stability decreased in the presence of ERK and p38 MAPK, but not the JNK, inhibitors. These results indicate that regulation of CD38 expression through p38 and JNK MAPKs involves NF-kappaB and AP-1 activation, and ERK and p38 MAPKs also regulate expression posttranscriptionally through message stability.

TLR2 Utilization ofBorreliaDoes Not Induce p38- and IFN-β Autocrine Loop-Dependent Expression of CD38, Resulting in Poor Migration and Weak IL-12 Secretion of Dendritic Cells

“…TNF-a induces activation of ERK, p38, and JNK MAPKs, and p38 and JNK MAPKs regulate CD38 activation through activating NF-kB and AP-1 (20). A recent study by Frasca et al (21) showed that LPS-induced CD38 upregulation in human DCs can be inhibited efficiently by p38 inhibition and, to a lesser degree, by ERK inhibition.…”

“…To understand the different responses of DCs to borreliae versus E. coli and to uncover possible mechanisms that result in defective CD38 expression in B. garinii DCs, we investigated the role of different signaling pathways in the upregulation of CD38. Regulation of CD38 expression has previously been associated with p38 MAPK in human DCs, neutrophils, and airway smooth muscle cells (19)(20)(21). We used various MAPK inhibitors to study the importance of ERK, JNK, and p38 pathways in CD38 upregulation.…”

Calcium Signaling in Airway Smooth Muscle

“…These findings indicate that TNF-a augments the sensitivity of HASM cells to spasmogens by up-regulating the expression of CD38. Further studies demonstrated that the up-regulation of CD38 by TNF-a is mediated through the transcription factors NF-kB and AP-1 and involves the MAP kinases (92,93). White and colleagues reported a significantly increased expression of TRPC3 after TNF-a treatment of ASM cells (32).…”

Brain-Derived Neurotrophic Factor in TNF-α Modulation of Ca2+ in Human Airway Smooth Muscle

“…ASM contractility is normally determined by regulation of intracellular Ca 21 ([Ca 21 ] i ), which, in turn, involves several mechanisms, including sarcoplasmic reticulum (SR) Ca 21 release and Ca 21 influx (1-3). With airway inflammation induced by cytokines such as TNF-a, several of these regulatory mechanisms may be altered, thus contributing to increased ASM contractility (4)(5)(6)(7)(8).…”