Skip to main content

Advertisement

SpringerLink
Log in

G-Protein-coupled receptor agonists differentially regulate basal or tumor necrosis factor-α-stimulated activation of interleukin-6 and RANTES in human airway smooth muscle cells

  • Published:
Journal of Biomedical Science

Summary

Using thapsigargin (Tg), an agent that mobilizes calcium by directly emptying intracellular stores, we previously showed that intracellular calcium may play an important role in the regulation of intercellular adhesion molecule (ICAM)-1 gene expression induced by cytokines in human airway smooth muscle (ASM) cells. In the present study, we extended this previous observation by comparing the effect of Tg and other calcium-mobilizing G-protein-coupled receptor (GPCR) agonists on the expression of different pro-inflammatory genes in response to tumor necrosis factor (TNF)-α in ASM cells. We found that in resting cells, Tg (10–100 nM) or the bradykinin (BK) (1–10 μM) and thrombin (Thr) (1 U/ml) stimulated interleukin (IL)-6 secretion but had no effect on regulated on activation, normal T cells expressed and secreted (RANTES) levels. More importantly, such calcium-mobilizing agents significantly enhanced TNF-α-induced IL-6 secretion while RANTES secretion was abrogated. The use of luciferase-tagged IL-6 and RANTES promoter constructs demonstrated similar effects of Tg on IL-6 and RANTES genes in basal and TNF-α-stimulated conditions. The cyclic adenosine monophosphate (cAMP)-dependent pathway plays a minor role in this differential regulation of IL-6 and RANTES genes expression. 2-Aminoethoxydiphenyl borate (APB), a blocker of store-operated calcium channels (SOCs), and bisindolylmaleimide I (Bis I), a broad-spectrum protein kinase C (PKC) inhibitor, inhibited the basal and synergic effects of IL-6 secretion in response to calcium-mobilizing agents and TNF-α, but did not prevent the abrogated effect of RANTES secretion. We also found that Go-6976, a selective calcium-dependent PKC isozyme inhibitor, did not inhibit IL-6 secretion in response to GPCR agonist and TNF-α; whereas Rottlerlin, a PKC-δ inhibitor, inhibited both Thr- and TNF-α-induced expression of IL-6, while BK-induced IL-6 secretion was not affected. Interestingly, TNF-α-induced interferon regulatory factor (IRF)-1 activation was significantly inhibited by all calcium-mobilizing agents, BK, Thr and Tg. These results show that calcium-mobilizing GPCR agonists functionally interact with TNF-α to differentially regulate pro-inflammatory genes expression in human ASM cells, possibly by involving Tg-sensitive intracellular calcium stores, SOC and PKC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Berridge M.J., Bootman M.D. and Lipp P. (1998) Calcium–a life and death signal. Nature 395: 645–648

    Article  PubMed  CAS  Google Scholar 

  2. Schwaninger M., Sallmann S., Petersen N., Schneider A., Prinz S., Libermann T.A. and Spranger M. (1999) Bradykinin induces interleukin-6 expression in astrocytes through activation of nuclear factor-kappaB. J. Neurochem. 73:1461–1466

    Article  PubMed  CAS  Google Scholar 

  3. Amrani Y., Chen H. and Panettieri R.A. Jr. (2000) Activation of tumor necrosis factor receptor 1 in airway smooth muscle: a potential pathway that modulates bronchial hyperresponsiveness in asthma? Respir. Res. 1: 49–53

    Article  PubMed  CAS  Google Scholar 

  4. Panettieri R.A., Murray R.K., DePalo L.R., Yadvish P.A. and Kotlikoff M.I. (1989) A human airway smooth muscle cell line that retains physiological responsiveness. Am. J. Physiol. 256: C329–335

    PubMed  CAS  Google Scholar 

  5. Amrani Y., Da Silva A., Kassel O. and Bronner C. (1994) Biphasic increase in cytosolic free calcium induced by bradykinin and histamine in cultured tracheal smooth muscle cells: is the sustained phase artifactual? Naunyn Schmiedebergs Arch Pharmacol. 350: 662–669

    Article  PubMed  CAS  Google Scholar 

  6. Amrani Y., Magnier C., Enouf J., Wuytack F. and Bronner C. (1995) Ca2+ increase and Ca(2+)-influx in human tracheal smooth muscle cells: role of Ca2+ pools controlled by sarco-endoplasmic reticulum Ca(2+)-ATPase 2 isoform. Br. J. Phannacol. 115:1204–1210

    PubMed  CAS  Google Scholar 

  7. Tolloczko B., Jia Y.L. and Martin J.G. (1995) Serotonin-evoked calcium transients in airway smooth muscle cells. Am. J. Physiol. 269: L234–240

    PubMed  CAS  Google Scholar 

  8. Liu X. and Farley J.M. (1996) Depletion and refilling of acetylcholine- and caffeine-sensitive Ca2+ stores in tracheal myocytes. J. Pharmacol. Exp. Ther. 277:789–795

    PubMed  CAS  Google Scholar 

  9. Yang C.M. (1998) Dissociation of intracellular Ca2+ release and Ca2+ entry response to 5-hydroxytryptamine in cultured canine tracheal smooth muscle cells. Cell Signal 10: 735–742

    Article  PubMed  CAS  Google Scholar 

  10. Berger P., Tunon-De-Lara J.M., Savineau J.P. and Marthan R., (2001) Selected contribution: tryptase-induced PAR-2-mediated Ca(2+) signaling in human airway smooth muscle cells. J. Appl. Physiol. 91: 995–1003

    PubMed  CAS  Google Scholar 

  11. Amrani Y., Panettieri R. A., Jr., Frossard N. and Bronner C. (1996) Activation of the TNF alpha-p55 receptor induces myocyte proliferation and modulates agonist-evoked calcium transients in cultured human tracheal smooth muscle cells. Am. J. Respir. Cell Mol. Biol. 15: 55–63

    PubMed  CAS  Google Scholar 

  12. Peiretti F., Fossat C., Anfosso F., Alessi M. C., Henry M., Juhan-Vague I. and Nalbone G. (1996) Increase in cytosolic calcium upregulates the synthesis of type 1 plasminogen activator inhibitor in the human histiocytic cell line U937. Blood 87:162–173

    PubMed  CAS  Google Scholar 

  13. Amrani Y., Krymskaya V., Maki C. and Panettieri R. A., Jr., (1997) Mechanisms underlying TNF-alpha effects on agonist-mediated calcium homeostasis in human airway smooth muscle cells. Am. J. Physiol. 273: L1020–1028

    PubMed  CAS  Google Scholar 

  14. Panettieri R.A., Jr. (2003) Airway smooth muscle: immunomodulatory cells that modulate airway remodeling? Respir. Physiol. Neurobiol. 137:277–293

    Article  PubMed  CAS  Google Scholar 

  15. Amrani Y., Lazaar A.L., Hoffman R., Amin K., Ousmer S. and Panettieri R.A., Jr. (2000) Activation of p55 tumor necrosis factor-alpha receptor-1 coupled to tumor necrosis factor receptor-associated factor 2 stimulates intercellular adhesion molecule-1 expression by modulating a thapsigargin-sensitive pathway in human tracheal smooth muscle cells. Mol. Pharmacol. 58: 237–245

    PubMed  CAS  Google Scholar 

  16. Terry C.M., Clikeman J.A., Hoidal J.R. and Callahan K.S. (1999) TNF-alpha and IL-1alpha induce heme oxygenase-1 via protein kinase C, Ca2+, and phospholipase A2 in endothelial cells. Am. J. Physiol. 276:H1493–501

    PubMed  CAS  Google Scholar 

  17. Denecker G., Vandenabeele P., Grooten J., Penning L.C., Declercq W., Beyaert R., Buurman W. A. and Fiers W. (1997) Differential role of calcium in tumour necrosis factormediated apoptosis and secretion of granulocyte-macrophage colony-stimulating factor in a T cell hybridoma. Cytokine 9:631–638

    Article  PubMed  CAS  Google Scholar 

  18. Quinlan K.L., Naik S.M., Cannon G., Armstrong C.A., Bunnett N.W., Ansel J.C. and Caughrnan S.W. (1999) Substance P activates coincident NF-AT- and NF-kappa B-dependent adhesion molecule gene expression in microvascular endothelial cells through intracellular calcium mobilization. J. Immunol. 163:5656–5665

    PubMed  CAS  Google Scholar 

  19. Triggiani M., Gentile M., Secondo A., Granata F., Oriente A., Taglialatela M., Annunziato L. and Marone G. (2001) Histamine induces exocytosis and IL-6 production from human lung macrophages through interaction with H1 receptors. J. Immunol. 166:4083–4091

    PubMed  CAS  Google Scholar 

  20. Huang C.D., Tliba O., Panettieri R.A., Jr and Amrani Y. (2003) Bradykinin induces interleukin-6 production in human airway smooth muscle cells: modulation by Th2 cytokines and dexamethasone. Am. J. Respir. Cell. Mol. Biol. 28: 330–338

    Article  PubMed  CAS  Google Scholar 

  21. Zhu Y.M., Bradbury D.A., Pang L. and Knox A.J. (2003) Transcriptional regulation of interleukin (IL)-8 by bradykinin in human airway smooth muscle cells involves prostanoid-dependent activation of AP-1 and nuclear factor (NF)-IL-6 and prostanoid-independent activation of NF-kappaB. J. Biol. Chem. 278: 29366–29375

    Article  PubMed  CAS  Google Scholar 

  22. Ammit A.J., Hoffman R.K., Amrani Y., Lazaar A.L., Hay D.W., Torphy T.J., Penn R.B. and Panettieri R. A., Jr. (2000) Tumor necrosis factor-alpha-induced secretion of RANTES and interleukin-6 from human airway smooth-muscle cells. Modulation by cyclic adenosine monophosphate. Am. J. Respir. Cell Mol. Biol. 23: 794–802

    PubMed  CAS  Google Scholar 

  23. Eickelberg O., Pansky A., Mussmann R., Bihl M., Tamm M., Hildebrand P., Perruchoud A. P. and Roth M. (1999) Transforming growth factor-beta 1 induces interleukin-6 expression via activating protein-1 consisting of JunD homodimers in primary human lung fibroblasts. J. Biol. Chem. 274: 12933–12938

    Article  PubMed  CAS  Google Scholar 

  24. Ammit A. J., Lazaar A. L., Irani C., O’Neill G. M., Gordon N. D., Amrani Y., Penn R. B. and Panettieri R. A., Jr. (2002) Tumor necrosis factor-alpha-induced secretion of RANTES and interleukin-6 from human airway smooth muscle cells: modulation by glucocorticoids and beta-agonists. Am. J. Respir. Cell Mol. Biol. 26:465–474

    PubMed  CAS  Google Scholar 

  25. Moriuchi H., Moriuchi M. and Fauci A. S. (1997) Nuclear factor-kappa B potently up-regulates the promoter activity of RANTES, a chernokine that blocks HIV infection. J. Immunol. 158: 3483–3491

    PubMed  CAS  Google Scholar 

  26. Krymskaya V. P., Penn R. B., Orsini M. J., Scott P. H., Plevin R. J,, Walker T. R., Eszterhas A. J., Amrani Y., Chilvers E. R. and Panettieri R. A., Jr. (1999) Phosphatidylinositol 3-kinase mediates mitogen-induced human airway smooth muscle cell proliferation. Am. J. Physiol. 277: L65–78

    PubMed  CAS  Google Scholar 

  27. Tliba O., Tliba S., Huang C. D., Hoffman R. K., DeLong P., Panettieri R. A., Jr, and Amrani Y. (2003) Tumor necrosis factor alpha modulates airway smooth muscle function via the autocrine action of interferon beta. J. Biol. Chem. 278: 50615-50623

    Article  PubMed  CAS  Google Scholar 

  28. Amrani Y., Ammit A. J. and Panettieri R. A., 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: 646–655

    PubMed  CAS  Google Scholar 

  29. Meldolesi J. and Pozzan T. (1998) The heterogeneity of ER Ca2+ stores has a key role in nonmuscle cell signaling and function. J. Cell Bio1. 142: 1395–1398

    Article  PubMed  CAS  Google Scholar 

  30. Amrani Y. and Panettieri R. A., Jr. (1998) Cytokines induce airway smooth muscle cell hyperresponsiveness to contractile agonists. Thorax 53: 713–716

    Article  PubMed  CAS  Google Scholar 

  31. Bost K. L. and Mason M. J. (1995) Thapsigargin and cyclopiazonic acid initiate rapid and dramatic increases of IL-6 inRNA expression and IL-6 secretion in murine peritoneal macrophages. J. Immunol. 155: 285–296

    PubMed  CAS  Google Scholar 

  32. Janssen L. J. (2002) Ionic mechanisms and Ca(2+) regulation in airway smooth muscle contraction: do the data contradict dogma? Am. J. Physiol. Lung Cell Mol. Physiol. 282: L1161–1178

    PubMed  CAS  Google Scholar 

  33. Bootman M. D., Collins T. J., Mackenzie L., Roderick H. L., Berridge M. J. and Peppiatt C. M. (2002) 2-aminoethoxydiphenyl borate (2-APB) is a reliable Mocker of store-operated Ca2+ entry but an inconsistent inhibitor of InsP3-induced Ca2+ release. FASEB J. 16: 1145–1150

    Article  PubMed  CAS  Google Scholar 

  34. Webb B. L, Hirst S. J, and Giembycz M. A. (2000) Protein kinase C isoenzymes: a review of their structure, regulation and role in regulating airways smooth muscle tone and mitogenesis, Br. J. Pharmacol. 130:1433–1452

    Article  PubMed  CAS  Google Scholar 

  35. Knox A. J., Corbett L., Stocks J., Holland E., Zhu Y. M. and Pang L. (2001) Human airway smooth muscle cells secrete vascular endothelial growth factor: up-regulation by bradykinin via a protein kinase C and prostanoid-dependent mechanism. FASEB J. 15: 2480–2488

    Article  PubMed  CAS  Google Scholar 

  36. Pang L., Nie M., Corbett L., Donnelly R., Gray S. and Knox A. J. (2002) Protein kinase C-epsilon mediates bradykinin-induced cyclooxygenase-2 expression in human airway smooth muscle cells. FASEB J. 16: 1435–1437

    PubMed  CAS  Google Scholar 

  37. Genin P., Algarte M., Roof P., Lin R. and Hiscott J. (2000) Regulation of RANTES chemokine gene expression requires cooperativity between NF-kappa B and IFN-regulatory factor transcription factors. J. Immunol. 164: 5352–5361

    PubMed  CAS  Google Scholar 

  38. Lee A. H., Hong J. H. and Seo Y. S. (2000) Tumour necrosis factor-alpha and interferon-gamma synergistically activate the RANTES promoter through nuclear factor kappaB and interferon regulatory factor 1 (IRF-1) transcription factors. Biochem. J. 350 Pt 1:131–138

    Article  PubMed  CAS  Google Scholar 

  39. Andoh A., Fujino S., Bamba S., Araki Y., Okuno T., Bamba T. and Fujiyama Y. (2002) IL-17 selectively down-regulates TNF-alpha-induced RANTES gene expression in human colonic subepithelial myofibroblasts. J. Immunol. 169: 1683–1687

    PubMed  CAS  Google Scholar 

  40. Maruoka S., Hashimoto S., Gon Y., Takeshita I. and Horie T. (2000) PAF-induced RANTES production by human airway smooth muscle cells requires both p38 MAP kinase and Eric Am. J. Respir. Crit. Care Med. 161: 922–929

    PubMed  CAS  Google Scholar 

  41. Thastrup O., Cullen P. J., Drobak B. K., Hanley M. R. and Dawson A. P. (1990) Thapsigargin, a tumor promoter, discharges intracellular Ca2+ stores by specific inhibition of the endoplasmic reticulum Ca2(+)-ATPase. Proc. Natl. Acad. Sci. USA 87: 2466–2470

    Article  PubMed  CAS  Google Scholar 

  42. Marriott I., Bost K. L. and Mason M. J. (1998) Differential kinetics for induction of interleukin-6 mRNA expression in murine peritoneal macrophages: evidence for calcium-dependent and independent-signalling pathways. J. Cell Physiol. 177:232–240

    Article  PubMed  CAS  Google Scholar 

  43. Pyne N. J., Tolan D. and Pyne S. (1997) Bradykinin stimulates cAMP synthesis via mitogen-activated protein kinase-dependent regulation of cytosolic phospholipase A2 and prostaglandin E2 release in airway smooth muscle. Biochem. J. 328(Pt 2):689–694

    PubMed  CAS  Google Scholar 

  44. Pang L. and Knox A. J. (1997) PGE2 release by bradykinin in human airway smooth muscle cells: involvement of cyclooxygenase-2 induction. Am. J. Physiol. 273: L1132–1140

    PubMed  CAS  Google Scholar 

  45. Kotlikoff M. I., Herrera G. and Nelson M. T. (1999) Calcium penneant ion channels in smooth muscle. Rev. Physiol. Biochem. Pharmacol. 134: 147–199

    PubMed  CAS  Google Scholar 

  46. Parekh A. B. and Penner R. (1997) Store depletion and calcium influx. Physiol. Rev. 77: 901–930

    PubMed  CAS  Google Scholar 

  47. Murray R. K. and Kotlikoff M I. (1991) Receptor-activated calcium influx in human airway smooth muscle cells. J. Physiol. 435: 123–144

    PubMed  CAS  Google Scholar 

  48. Parekh A. B., Fleig A. and Penner R. (1997) The store-operated calcium current I(CRAC): nonlinear activation by InsP3 and dissociation from calcium release. Cell 89: 973–980

    Article  PubMed  CAS  Google Scholar 

  49. Marthan R. (2004) Store-operated calcium entry and intracellular calcium release channels in airway smooth muscle. Am. J. Physiol. Lung Cell Mot. Physiol. 286: L907–908

    Article  PubMed  CAS  Google Scholar 

  50. Sweeney M., McDaniel S. S., Platoshyn O., Zhang S., Yu Y., Lapp B. R., Zhao Y., Thistlethwaite P. A. and Yuan J. X. (2002) Role of capacitative Ca2+ entry in bronchial contraction and remodeling. J. Appl. Physiol. 92: 1594–1602

    PubMed  CAS  Google Scholar 

  51. Maruyama T., Kanaji T., Nakade S., Kanna T. and Mikoshiba K. (1997) 2-APB, 2-aminoethoxydiphenyl borate, a membrane-penetrable modulator of Ins(1,4,5)P3-induced Ca2+ release. J. Biochem. (Tokyo) 122: 498–505

    CAS  Google Scholar 

  52. Gregory R. B., Rychkov G. and Barritt G. J. (2001) Evidence that 2-aminoethyl diphenylborate is a novel inhibitor of store-operated Ca2+ channels in liver cells, and acts through a mechanism which does not involve inositol trisphosphate receptors. Biochem. J. 354: 285–290

    Article  PubMed  CAS  Google Scholar 

  53. Yang K. X. and Black J. L. (1996) Protein kinase C induced changes in human airway smooth muscle tone: the effects of Ca2+ and Na+ transport. Eur. J. Pharmacol. 315: 65–71

    Article  PubMed  CAS  Google Scholar 

  54. Lin C. C., Shyr M. H., Chien C. S., Wang C. C., Chiu C. T., Hsiao L. D. and Yang C. M. (2002) Thrombin-stimulated cell proliferation mediated through activation of Ras/Raf/MEK/MAPK pathway in canine cultured tracheal smooth muscle cells. Cell Signal 14: 265–275

    Article  PubMed  CAS  Google Scholar 

  55. John M., Hirst S. J., Jose P. J., Robichaud A., Berkman N., Witt C., Twort C. H., Barnes P. J. and Chung K. F. (1997) Human airway smooth muscle cells express and release RANTES in response to T helper 1 cytokines: regulation by T helper 2 cytokines and corticosteroids. J. Immunol. 158: 1841–1847

    PubMed  CAS  Google Scholar 

  56. Tliba O., Panettieri R. A., Jr., Tliba S., Walseth T. P. and Amrani Y. (2004) Tumor necrosis factor-alpha differentially regulates the expression of proinflammatory genes in human airway smooth muscle cells by activation of interferon-beta-dependent CD38 pathway. Mot. Pharmacol. 66:322–329

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported, in part, by NSC 93-2314-B-182A-067-, National Science Council, Taiwan (Huang, CD) and through grants from the National Institutes of Health (RO1 -HL55301 to RAP and 2RO1-HL064063 to YA), and American Lung Association grant RG-062-N (YA). Yassine Amrani is a Parker B. Francis Fellow in Pulmonary Research.

Author information

Authors and Affiliations

  1. Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan

    Chien-Da Huang & Han-Pin Kuo

  2. Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pennsylvania Medical Center, 848 Biomedical Research Building II/III, 421 Curie Blvd., Philadelphia, PA, 19104-6160, USA

    Chien-Da Huang, Alaina J. Ammit, Omar Tliba, Raymond B. Penn, Reynold A. Panettieri Jr. & Yassine Amrani

Authors
  1. Chien-Da Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alaina J. Ammit
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Omar Tliba
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Han-Pin Kuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Raymond B. Penn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Reynold A. Panettieri Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yassine Amrani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yassine Amrani.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, CD., Ammit, A.J., Tliba, O. et al. G-Protein-coupled receptor agonists differentially regulate basal or tumor necrosis factor-α-stimulated activation of interleukin-6 and RANTES in human airway smooth muscle cells. J Biomed Sci 12, 763–776 (2005). https://doi.org/10.1007/s11373-005-9008-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11373-005-9008-z

Keywords

Search

Navigation