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

  • Joseph A. Jude
  • Reynold A. PanettieriJr
  • Timothy F. Walseth
  • Mathur S. Kannan
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 691)


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.


CD38 Expression Airway Smooth Muscle Airway Hyperresponsiveness Airway Smooth Muscle Cell Human Airway Smooth Muscle Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



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.


  1. 1.
    Adcock IM, Tsaprouni L, Bhavsar P et al (2007) Epigenetic regulation of airway inflammation. Curr Opin Immunol 19(6):694–700CrossRefPubMedGoogle Scholar
  2. 2.
    Albuquerque RV, Hayden CM, Palmer LJ et al (1998) Association of polymorphisms within the tumour necrosis factor (TNF) genes and childhood asthma. Clin Exp Allergy 28: 578–584CrossRefPubMedGoogle Scholar
  3. 3.
    Amrani Y, Ammit AJ, Panettieri RA Jr (2001) Tumor necrosis factor receptor (TNFR) 1, but not TNFR2, mediates tumor necrosis factor-alpha-induced interleukin-6 and RANTES in human airway smooth muscle cells: role of p38 and p42/44 mitogen-activated protein kinases. Mol Pharmacol 60:646–655PubMedGoogle Scholar
  4. 4.
    Antoniu SA (2009) Golimumab for severe asthma. Expert Opin Investig Drugs 18:1421–1423CrossRefPubMedGoogle Scholar
  5. 5.
    Barata H, Thompson M, Zielinska W et al (2004) The role of cyclic-ADP-ribose-signaling pathway in oxytocin-induced Ca2+ transients in human myometrium cells. Endocrinology 145:881–889CrossRefPubMedGoogle Scholar
  6. 6.
    Berry MA, Hargadon B, Shelley M et al (2006) Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med 354:697–708CrossRefPubMedGoogle Scholar
  7. 7.
    Bilolikar H, Nam AR, Rosenthal M et al (2005) Tumour necrosis factor gene polymorphisms and childhood wheezing. Eur Respir J 26:637–646CrossRefPubMedGoogle Scholar
  8. 8.
    Bousquet J, Jacot W, Yssel H et al (2004) Epigenetic inheritance of fetal genes in allergic asthma. Allergy 59(2):138–147CrossRefPubMedGoogle Scholar
  9. 9.
    Broide DH, Lotz M, Cuomo AJ et al (1992) Cytokines in symptomatic asthma airways. J Allergy Clin Immunol 89:958–967CrossRefPubMedGoogle Scholar
  10. 10.
    Chue SC, Seow CJ, Duan W et al (2004) Inhibitor of p42/44 mitogen-activated protein kinase, but not p38 MAPK, attenuated antigen challenge of guinea pig airways in vitro. Int Immunopharmacol 4:1089–1098CrossRefPubMedGoogle Scholar
  11. 11.
    Deshpande DA, Dogan S, Walseth TF et al (2004) Modulation of calcium signaling by interleukin-13 in human airway smooth muscle: role of CD38/cyclic adenosine diphosphate ribose pathway. Am J Respir Cell Mol Biol 31:36–42CrossRefPubMedGoogle Scholar
  12. 12.
    Deshpande DA, Walseth TF, Panettieri RA et al (2003) CD38/cyclic ADP-ribose-mediated Ca2+ signaling contributes to airway smooth muscle hyper-responsiveness. FASEB J 17:452–454PubMedGoogle Scholar
  13. 13.
    Deshpande DA, White TA, Dogan S et al (2005a) CD38/cyclic ADP-ribose signaling: role in the regulation of calcium homeostasis in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 288, L773–L788CrossRefPubMedGoogle Scholar
  14. 14.
    Deshpande DA, White TA, Guedes AG et al (2005b) Altered airway responsiveness in CD38-deficient mice. Am J Respir Cell Mol Biol 32:149–156CrossRefPubMedGoogle Scholar
  15. 15.
    Desmet C, Gosset P, Henry E et al (2005) Treatment of experimental asthma by decoy-mediated local inhibition of activator protein-1. Am J Respir Crit Care Med 172:671–678CrossRefPubMedGoogle Scholar
  16. 16.
    Desmet C, Gosset P, Pajak B et al (2004) Selective blockade of NF-kappa B activity in airway immune cells inhibits the effector phase of experimental asthma. J Immunol 173:5766–5775PubMedGoogle Scholar
  17. 17.
    Dipp M, Evans AM (2001) Cyclic ADP-ribose is the primary trigger for hypoxic pulmonary vasoconstriction in the rat lung in situ. Circ Res 89:77–83CrossRefPubMedGoogle Scholar
  18. 18.
    Duan W, Chan JH, McKay K et al (2005). Inhaled p38alpha mitogen-activated protein kinase antisense oligonucleotide attenuates asthma in mice. Am J Respir Crit Care Med 171:571–578CrossRefPubMedGoogle Scholar
  19. 19.
    Durig J, Naschar M, Schmucker U et al (2002) CD38 expression is an important prognostic marker in chronic lymphocytic leukaemia. Leukemia 16:30–35CrossRefPubMedGoogle Scholar
  20. 20.
    Edwards MR, Bartlett NW, Clarke D et al (2009) Targeting the NF-kappaB pathway in asthma and chronic obstructive pulmonary disease. Pharmacol Ther 121:1–13CrossRefPubMedGoogle Scholar
  21. 21.
    Erin EM, Leaker BR, Nicholson GC et al (2006) The effects of a monoclonal antibody directed against tumor necrosis factor-alpha in asthma. Am J Respir Crit Care Med 174:753–762CrossRefPubMedGoogle Scholar
  22. 22.
    Erzurum SC (2006) Inhibition of tumor necrosis factor alpha for refractory asthma. N Engl J Med 354:754–758CrossRefPubMedGoogle Scholar
  23. 23.
    Ferrero E, Saccucci F, Malavasi F (1999) The human CD38 gene: polymorphism, CpG island, and linkage to the CD157 (BST-1) gene. Immunogenetics 49:597–604CrossRefPubMedGoogle Scholar
  24. 24.
    Frishman JI, Edwards CK, Sonnenberg MG et al (2000) Tumor necrosis factor (TNF)-alpha-induced interleukin-8 in human blood cultures discriminates neutralization by the p55 and p75 TNF soluble receptors. J Infect Dis 182:1722–1730CrossRefPubMedGoogle Scholar
  25. 25.
    Graeff R, Liu Q, Kriksunov IA et al (2006) Acidic residues at the active sites of CD38 and ADP-ribosyl cyclase determine nicotinic acid adenine dinucleotide phosphate (NAADP) synthesis and hydrolysis activities. J Biol Chem 281:28951–28957CrossRefPubMedGoogle Scholar
  26. 26.
    Graeff R, Liu Q, Kriksunov IA et al (2009) Mechanism of cyclizing NAD to cyclic ADP-ribose by ADP-ribosyl cyclase and CD38. J Biol Chem 284 (40):27629–27636CrossRefPubMedGoogle Scholar
  27. 27.
    Guedes AG, Jude JA, Paulin J (2008) Role of CD38 in TNF-alpha-induced airway hyperresponsiveness. Am J Physiol Lung Cell Mol Physiol 294, L290–L299CrossRefPubMedGoogle Scholar
  28. 28.
    Guedes AG, Paulin J, Rivero-Nava L (2006) CD38-deficient mice have reduced airway hyperresponsiveness following IL-13 challenge. Am J Physiol Lung Cell Mol Physiol 291:L1286–L1293CrossRefPubMedGoogle Scholar
  29. 29.
    Hart LA, Krishnan VL, Adcock IM et al (1998) Activation and localization of transcription factor, nuclear factor-kappaB, in asthma. Am J Respir Crit Care Med 158:1585–1592PubMedGoogle Scholar
  30. 30.
    Higashida H, Hashii M, Yokoyama S et al (2001) Cyclic ADP-ribose as a potential second messenger for neuronal Ca2+ signaling. J Neurochem 76:321–331CrossRefPubMedGoogle Scholar
  31. 31.
    Holgate ST, Yang Y, Haitchi HM et al (2006) The genetics of asthma: ADAM33 as an example of a susceptibility gene. Proc Am Thoracic Soc 3(5):440–443CrossRefGoogle Scholar
  32. 32.
    Howard M, Grimaldi JC, Bazan JF et al (1993) Formation and hydrolysis of cyclic ADP-ribose catalyzed by lymphocyte antigen CD38. Science 262:1056–1059CrossRefPubMedGoogle Scholar
  33. 33.
    Howarth PH, Babu KS, Arshad HS et al (2005) Tumour necrosis factor (TNF)-alpha as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax 60:1012–1018CrossRefPubMedGoogle Scholar
  34. 34.
    Ikehata F, Satoh J, Nata K et al (1998) Autoantibodies against CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) that impair glucose-induced insulin secretion in noninsulin- dependent diabetes patients. J Clin Invest 102:395–401CrossRefPubMedGoogle Scholar
  35. 35.
    Issa R, Xie S, Lee KY et al (2006) GRO-alpha regulation in airway smooth muscle by IL-1beta and TNF-alpha: role of NF-kappaB and MAP kinases. Am J Physiol Lung Cell Mol Physiol 291:L66–L74CrossRefPubMedGoogle Scholar
  36. 36.
    Kang BN, Deshpande DA, Tirumurugaan KG et al (2005) Adenoviral mediated anti-sense CD38 attenuates TNF-alpha-induced changes in calcium homeostasis of human airway smooth muscle cells. Can J Physiol Pharmacol 83:799–804CrossRefPubMedGoogle Scholar
  37. 37.
    Kang BN, Jude JA, Panettieri RA Jr et al (2008) Glucocorticoid regulation of CD38 expression in human airway smooth muscle cells: role of dual specificity phosphatase 1. Am J Physiol Lung Cell Mol Physiol 295, L186–L193CrossRefPubMedGoogle Scholar
  38. 38.
    Kang BN, Tirumurugaan KG, Deshpande DA et al (2006) Transcriptional regulation of CD38 expression by tumor necrosis factor-alpha in human airway smooth muscle cells: role of NF-kappaB and sensitivity to glucocorticoids. FASEB J 20, E170–E179Google Scholar
  39. 39.
    Kishimoto H, Hoshino S, Ohori M et al (1998) Molecular mechanism of human CD38 gene expression by retinoic acid. Identification of retinoic acid response element in the first intron. J Biol Chem 273:15429–15434CrossRefPubMedGoogle Scholar
  40. 40.
    Lee HC (2000) Enzymatic functions and structures of CD38 and homologs. Chem Immunol 75:39–59CrossRefPubMedGoogle Scholar
  41. 41.
    Lee HC, Aarhus R (1991) ADP-ribosyl cyclase: an enzyme that cyclizes NAD+ into a calcium-mobilizing metabolite. Cell Regul 2:203–209PubMedGoogle Scholar
  42. 42.
    Li YF, Gauderman WJ, Avol E et al (2006) Associations of tumor necrosis factor G-308A with childhood asthma and wheezing. Am J Respir Crit Care Med 173:970–976CrossRefPubMedGoogle Scholar
  43. 43.
    Liu Q, Graeff R, Kriksunov IA et al (2009) Structural basis for enzymatic evolution from a dedicated ADP-ribosyl cyclase to a multi- functional NAD hydrolase. J Biol Chem 284(40):27637–27645CrossRefPubMedGoogle Scholar
  44. 44.
    Liu W, Liang Q, Balzar S et al (2008) Cell-specific activation profile of extracellular signal-regulated kinase 1/2, Jun N-terminal kinase, and p38 mitogen-activated protein kinases in asthmatic airways. J Allergy Clin Immunol 121:893–902CrossRefPubMedGoogle Scholar
  45. 45.
    Malavasi F, Deaglio S, Funaro A et al (2008) Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol Rev 88:841–886CrossRefPubMedGoogle Scholar
  46. 46.
    Matsuoka T, Kajimoto Y, Watada H et al (1995) Expression of CD38 gene, but not of mitochondrial glycerol-3-phosphate dehydrogenase gene, is impaired in pancreatic islets of GK rats. Biochem Biophys Res Commun 214:239–246CrossRefPubMedGoogle Scholar
  47. 47.
    Nata K, Takamura T, Karasawa T et al (1997) Human gene encoding CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase): organization, nucleotide sequence and alternative splicing. Gene 186:285–292CrossRefPubMedGoogle Scholar
  48. 48.
    Newton R, Hart LA, Stevens DA et al (1998) Effect of dexamethasone on interleukin-1beta-(IL-1beta)-induced nuclear factor-kappaB (NF-kappaB) and kappaB-dependent transcription in epithelial cells. Eur J Biochem 254:81–89CrossRefPubMedGoogle Scholar
  49. 49.
    Newton R, Holden NS, Catley MC et al (2007) Repression of inflammatory gene expression in human pulmonary epithelial cells by small-molecule IkappaB kinase inhibitors. J Pharmacol Exp Ther 321:734–742CrossRefPubMedGoogle Scholar
  50. 50.
    Noguchi N, Takasawa S, Nata K et al (1997) Cyclic ADP-ribose binds to FK506-binding protein 12.6 to release Ca2+ from islet microsomes. J Biol Chem 272:3133–3136CrossRefPubMedGoogle Scholar
  51. 51.
    Ortolan E, Vacca P, Capobianco A et al (2002) CD157, the Janus of CD38 but with a unique personality. Cell Biochem Funct 20:309–322CrossRefPubMedGoogle Scholar
  52. 52.
    Perera F, Tang WY, Herbstman J et al (2009) Relation of DNA methylation of 5'-CpG island of ACSL3 to transplacental exposure to airborne polycyclic aromatic hydrocarbons and childhood asthma. PLoS One 4(8) doi: 10.1371/annotation/6a678269-9623-4a13-8b19-4e9431ff3cb6Google Scholar
  53. 53.
    Prakash YS, Kannan MS, Walseth TF et al (1998) Role of cyclic ADP-ribose in the regulation of [Ca2+]i in porcine tracheal smooth muscle Am J Physiol 274:C1653–C1660PubMedGoogle Scholar
  54. 54.
    Schottelius AJ, Moldawer LL, Dinarello CA et al (2004) Biology of tumor necrosis factor-alpha- implications for psoriasis. Exp Dermatol 13:193–222CrossRefPubMedGoogle Scholar
  55. 55.
    Sieck GC, White TA, Thompson MA et al (2008) Regulation of store-operated Ca2+ entry by CD38 in human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 294:L378–L385CrossRefPubMedGoogle Scholar
  56. 56.
    Sun L, Iqbal J, Zaidi S et al (2006) Structure and functional regulation of the CD38 promoter. Biochem Biophys Res Commun 341:804–809CrossRefPubMedGoogle Scholar
  57. 57.
    Tang WX, Chen YF, Zou AP et al (2002) Role of FKBP12.6 in cADPR-induced activation of reconstituted ryanodine receptors from arterial smooth muscle. Am J Physiol Heart Circ Physiol 282:H1304–H310PubMedGoogle Scholar
  58. 58.
    Thomas PS (2001) Tumour necrosis factor-alpha: the role of this multifunctional cytokine in asthma. Immunol Cell Biol 79:132–140CrossRefPubMedGoogle Scholar
  59. 59.
    Thomas PS, Yates DH, Barnes PJ (1995) Tumor necrosis factor-alpha increases airway responsiveness and sputum neutrophilia in normal human subjects. Am J Respir Crit Care Med 152:76–80PubMedGoogle Scholar
  60. 60.
    Tirumurugaan KG, Jude JA, Kang BN et al (2007) TNF-alpha induced CD38 expression in human airway smooth muscle cells: role of MAP kinases and transcription factors NF-kappaB and AP-1. Am J Physiol Lung Cell Mol Physiol 292, L1385–L1395CrossRefPubMedGoogle Scholar
  61. 61.
    Tirumurugaan KG, Kang BN, Panettieri RA et al (2008) Regulation of the cd38 promoter in human airway smooth muscle cells by TNF-alpha and dexamethasone. Respir Res 9:26, doi: 10.1186/1465-9921-9-26.CrossRefPubMedGoogle Scholar
  62. 62.
    Wang CC, Lin WN, Lee CW et al (2005) Involvement of p42/p44 MAPK, p38 MAPK, JNK, and NF-kappaB in IL-1beta-induced VCAM-1 expression in human tracheal smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 288:L227–L237CrossRefPubMedGoogle Scholar
  63. 63.
    Wenzel SE, Barnes PJ, Bleecker ER et al (2009) A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma. Am J Respir Crit Care Med 179:549–558CrossRefPubMedGoogle Scholar
  64. 64.
    White TA, Kannan MS, Walseth TF (2003) Intracellular calcium signaling through the cADPR pathway is agonist specific in porcine airway smooth muscle. FASEB J 17:482–484PubMedGoogle Scholar
  65. 65.
    Ying S, Robinson DS, Varney V et al (1991) TNF alpha mRNA expression in allergic inflammation. Clin Exp Allergy 21:745–750CrossRefPubMedGoogle Scholar
  66. 66.
    Zhou L, Tan A, Iasvovskaia S et al (2003) Ras and mitogen-activated protein kinase kinase kinase-1 coregulate activator protein-1- and nuclear factor-kappaB-mediated gene expression in airway epithelial cells. Am J Respir Cell Mol Biol 28:762–769CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Joseph A. Jude
    • 1
  • Reynold A. PanettieriJr
    • 2
  • Timothy F. Walseth
    • 3
  • Mathur S. Kannan
    • 1
  1. 1.Department of Veterinary and Biomedical SciencesCollege of Veterinary Medicine, University of MinnesotaSt. PaulUSA
  2. 2.School of Medicine, University of PennsylvaniaPhiladelphiaUSA
  3. 3.Department of PharmacologyCollege of Veterinary Medicine, University of MinnesotaSt. PaulUSA

Personalised recommendations