TNF-α Regulation of CD38 Expression in Human Airway Smooth Muscle: Role of MAP Kinases and NF-κB
The pleiotropic cytokine TNF-α has been implicated in airway inflammation and airway hyperresponsiveness (AHR), hallmark features of asthma. Polymorphisms in the TNF gene cluster are associated with increased TNF-α production and risk of asthma. Our laboratory has demonstrated that in human airway smooth muscle (HASM) cells, TNF-α augments the expression of CD38, a type II transmembrane glycoprotein which synthesizes the calcium-mobilizing molecule cyclic ADP-ribose. Mice challenged intranasally with TNF-α develop AHR to inhaled methacholine. However, mice that are deficient in CD38 fail to develop AHR, indicating that CD38 expressed in the airways is required for cytokine-induced AHR. In HASM cells, TNF-α-induced CD38 expression is decreased in the presence of inhibitors of p38, JNK, and ERK mitogen-activated protein kinases (MAPKs). The decreased CD38 expression by p38 and JNK MAPK inhibitors is associated with decreased activation of NF-κB, whereas the decrease by the ERK MAPK inhibitor is due to decreased stability of CD38 transcripts. TNF-α induced a twofold activation of a 3 kb cd38 promoter following its transfection in HASM cells. However, there was no activation of the promoter lacking the NF-κB site. These results demonstrate that TNF-α regulation of CD38 expression in HASM cells is mediated transcriptionally through p38 and JNK MAPKs and NF-κB and post-transcriptionally through the ERK MAPK. These findings support a role for CD38/cADPR signaling in TNF-α-induced AHR.
KeywordsCD38 Expression Airway Smooth Muscle Airway Hyperresponsiveness Airway Smooth Muscle Cell Human Airway Smooth Muscle Cell
Work cited in this chapter is supported by grants from the National Institutes of Health (HL057498 to MSK) and (DA-11806 to TFW). We thank Drs. Tirumurugaan, Kang, and Guedes for their contribution.
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