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Advances in TNF Family Research pp 449–459Cite as

TNF-α Regulation of CD38 Expression in Human Airway Smooth Muscle: Role of MAP Kinases and NF-κB

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 691))

Abstract

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.

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Acknowledgments

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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Authors and Affiliations

  1. Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, 1971 Commonwealth Avenue, St. Paul, MN, 55108, USA

    Joseph A. Jude & Mathur S. Kannan

  2. School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Reynold A. Panettieri Jr

  3. Department of Pharmacology, College of Veterinary Medicine, University of Minnesota, 1971 Commonwealth Avenue, St. Paul, MN, 55108, USA

    Timothy F. Walseth

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  1. Joseph A. Jude
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  2. Reynold A. Panettieri Jr
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  3. Timothy F. Walseth
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  4. Mathur S. Kannan
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Correspondence to Mathur S. Kannan .

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Editors and Affiliations

  1. Dept. Biological Chemistry, Weizmann Institute of Science, 1 Herzl Street, Rehovot, 76100, Israel

    David Wallach

  2. Dept. Biological Chemistry, Weizmann Institute of Science, 1 Herzl Street, Rehovot, 76100, Israel

    Andrew Kovalenko

  3. Kennedy Institute of Rheumatology, Imperial College London, Aspenlea Rd. 1, London, W6 8LH, United Kingdom

    Marc Feldmann

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Jude, J.A., Panettieri, R.A., Walseth, T.F., Kannan, M.S. (2011). TNF-α Regulation of CD38 Expression in Human Airway Smooth Muscle: Role of MAP Kinases and NF-κB. In: Wallach, D., Kovalenko, A., Feldmann, M. (eds) Advances in TNF Family Research. Advances in Experimental Medicine and Biology, vol 691. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6612-4_46

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