Am. J. Respir. Cell Mol. Biol., Volume 23, Number 6, December, 2000 794-802

Tumor Necrosis Factor--Induced Secretion of RANTES and Interleukin-6 from Human Airway Smooth-Muscle Cells
Modulation by Cyclic Adenosine Monophosphate

Alaina J. Ammit, Rebecca K. Hoffman, Yassine Amrani, Aili L. Lazaar, Douglas W. P. Hay, Theodore J. Torphy, Raymond B. Penn, and Reynold A. Panettieri Jr.

Pulmonary Division, Department of Medicine, University of Pennsylvania; Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia; and SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania

Although 3':5' cyclic adenosine monophosphate (cAMP) is known to modulate cytokine production in a number of cell types, little information exists regarding cAMP-mediated effects on this synthetic function of human airway smooth-muscle (HASM) cells. We examined the effect of increasing intracellular cAMP concentration ([cAMP]_i) on tumor necrosis factor (TNF)--induced regulated on activation, normal T cells expressed and secreted (RANTES) and interleukin (IL)-6 secretion from cultured HASM cells. Pretreatment of HASM with prostaglandin (PG) E₂, forskolin, or dibutyryl cAMP inhibited TNF--induced RANTES secretion but increased TNF--induced IL-6 secretion. Moreover, stimulation with PGE₂, forskolin, or dibutyryl cAMP alone increased basal IL-6 secretion in a concentration-dependent manner. SB 207499, a specific phosphodiesterase type 4 inhibitor, augmented the inhibitory effects of PGE₂ and forskolin on TNF--induced RANTES. Collectively, these data demonstrate that increasing [cAMP]_i in HASM effectively increases IL-6 secretion but reduces RANTES secretion promoted by TNF-. Reverse transcriptase/polymerase chain reaction and ribonuclease protection assays suggested that these opposite effects of increased [cAMP]_i on TNF-- induced IL-6 and RANTES secretion may occur at the transcriptional level. Accordingly, we examined the effects of TNF-  and cAMP on the regulation of nuclear factor (NF)-B, a transcription factor known to modulate cytokine synthesis in numerous cell types. Stimulation of HASM cells with TNF- increased NF-B DNA-binding activity. However, increased [cAMP]_i in HASM neither activated NF-B nor altered TNF-- induced NF-B DNA-binding activity. These results were confirmed using a NF-B-luciferase reporter assay. Together, our data suggest that TNF--induced IL-6 and RANTES secretion may be associated with NF-B activation, and that inhibition of TNF--stimulated RANTES secretion and augmentation of IL-6 secretion by increased [cAMP]_i in HASM cells occurs via an NF-B-independent mechanism.

This article has been cited by other articles:

				A. E. John, Y. M. Zhu, C. E. Brightling, L. Pang, and A. J. Knox Human Airway Smooth Muscle Cells from Asthmatic Individuals Have CXCL8 Hypersecretion Due to Increased NF-{kappa}B p65, C/EBP{beta}, and RNA Polymerase II Binding to the CXCL8 Promoter J. Immunol., October 1, 2009; 183(7): 4682 - 4692. [Abstract] [Full Text] [PDF]

				M. Kaur, N. S. Holden, S. M. Wilson, M. B. Sukkar, K. F. Chung, P. J. Barnes, R. Newton, and M. A. Giembycz Effect of {beta}2-adrenoceptor agonists and other cAMP-elevating agents on inflammatory gene expression in human ASM cells: a role for protein kinase A Am J Physiol Lung Cell Mol Physiol, September 1, 2008; 295(3): L505 - L514. [Abstract] [Full Text] [PDF]

				T. Quante, Y. C. Ng, E. E. Ramsay, S. Henness, J. C. Allen, J. Parmentier, Q. Ge, and A. J. Ammit Corticosteroids Reduce IL-6 in ASM Cells via Up-Regulation of MKP-1 Am. J. Respir. Cell Mol. Biol., August 1, 2008; 39(2): 208 - 217. [Abstract] [Full Text] [PDF]

				M. Baroffio, E. Crimi, and V. Brusasco Review: Airway smooth muscle as a model for new investigative drugs in asthma Therapeutic Advances in Respiratory Disease, June 1, 2008; 2(3): 129 - 139. [Abstract] [PDF]

				R. B. Penn and J. L. Benovic Regulation of Heterotrimeric G Protein Signaling in Airway Smooth Muscle Proceedings of the ATS, January 1, 2008; 5(1): 47 - 57. [Abstract] [Full Text] [PDF]

				Y. Osawa, P. D. Yim, D. Xu, R. A. Panettieri, and C. W. Emala Raf-1 kinase mediates adenylyl cyclase sensitization by TNF-{alpha} in human airway smooth muscle cells Am J Physiol Lung Cell Mol Physiol, June 1, 2007; 292(6): L1414 - L1421. [Abstract] [Full Text] [PDF]

				J. Chhabra, Y-Z. Li, H. Alkhouri, A. E. Blake, Q. Ge, C. L. Armour, and J. M. Hughes Histamine and tryptase modulate asthmatic airway smooth muscle GM-CSF and RANTES release Eur. Respir. J., May 1, 2007; 29(5): 861 - 870. [Abstract] [Full Text] [PDF]

				R. Issa, S. Xie, K.-Y. Lee, R. D. Stanbridge, P. Bhavsar, M. B. Sukkar, and K. F. Chung GRO-{alpha} regulation in airway smooth muscle by IL-1beta and TNF-{alpha}: role of NF-{kappa}B and MAP kinases Am J Physiol Lung Cell Mol Physiol, July 1, 2006; 291(1): L66 - L74. [Abstract] [Full Text] [PDF]

				S. Henness, E. van Thoor, Q. Ge, C. L. Armour, J. M. Hughes, and A. J. Ammit IL-17A acts via p38 MAPK to increase stability of TNF-{alpha}-induced IL-8 mRNA in human ASM Am J Physiol Lung Cell Mol Physiol, June 1, 2006; 290(6): L1283 - L1290. [Abstract] [Full Text] [PDF]

				J. Kanefsky, M. Lenburg, and C.-M. Hai Cholinergic Receptor and Cyclic Stretch-Mediated Inflammatory Gene Expression in Intact ASM Am. J. Respir. Cell Mol. Biol., April 1, 2006; 34(4): 417 - 425. [Abstract] [Full Text] [PDF]

				K. F. Chung The Role of Airway Smooth Muscle in the Pathogenesis of Airway Wall Remodeling in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, November 1, 2005; 2(4): 347 - 354. [Abstract] [Full Text] [PDF]

				D. L. Clarke, M. G. Belvisi, S. J. Smith, E. Hardaker, M. H. Yacoub, K. K. Meja, R. Newton, D. M. Slater, and M. A. Giembycz Prostanoid receptor expression by human airway smooth muscle cells and regulation of the secretion of granulocyte colony-stimulating factor Am J Physiol Lung Cell Mol Physiol, February 1, 2005; 288(2): L238 - L250. [Abstract] [Full Text] [PDF]

				D. L. Clarke, M. G. Belvisi, E. Hardaker, R. Newton, and M. A. Giembycz E-Ring 8-Isoprostanes Are Agonists at EP2- and EP4-Prostanoid Receptors on Human Airway Smooth Muscle Cells and Regulate the Release of Colony-Stimulating Factors by Activating cAMP-Dependent Protein Kinase Mol. Pharmacol., February 1, 2005; 67(2): 383 - 393. [Abstract] [Full Text] [PDF]

				R. A. Panettieri Jr. Effects of Corticosteroids on Structural Cells in Asthma and Chronic Obstructive Pulmonary Disease Proceedings of the ATS, November 1, 2004; 1(3): 231 - 234. [Abstract] [Full Text] [PDF]

				H. Zhong, L. Belardinelli, T. Maa, I. Feoktistov, I. Biaggioni, and D. Zeng A2B Adenosine Receptors Increase Cytokine Release by Bronchial Smooth Muscle Cells Am. J. Respir. Cell Mol. Biol., January 1, 2004; 30(1): 118 - 125. [Abstract] [Full Text] [PDF]

				D. S. Faffe, T. Whitehead, P. E. Moore, S. Baraldo, L. Flynt, K. Bourgeois, R. A. Panettieri, and S. A. Shore IL-13 and IL-4 promote TARC release in human airway smooth muscle cells: role of IL-4 receptor genotype Am J Physiol Lung Cell Mol Physiol, October 1, 2003; 285(4): L907 - L914. [Abstract] [Full Text] [PDF]

				W.A. Wuyts, B.M. Vanaudenaerde, L.J. Dupont, M.G. Demedts, and G.M. Verleden Modulation by cAMP of IL-1{beta}-induced eotaxin and MCP-1 expression and release in human airway smooth muscle cells Eur. Respir. J., August 1, 2003; 22(2): 220 - 226. [Abstract] [Full Text] [PDF]

				Y. M. Zhu, D. A. Bradbury, L. Pang, and A. J. Knox 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-{kappa}B J. Biol. Chem., August 1, 2003; 278(31): 29366 - 29375. [Abstract] [Full Text] [PDF]

				C.-D. Huang, O. Tliba, R. A. Panettieri Jr., and Y. Amrani Bradykinin Induces Interleukin-6 Production in Human Airway Smooth Muscle Cells: Modulation by Th2 Cytokines and Dexamethasone Am. J. Respir. Cell Mol. Biol., March 1, 2003; 28(3): 330 - 338. [Abstract] [Full Text] [PDF]

				T. Lahiri, P. E. Moore, S. Baraldo, T. R. Whitehead, M. D. McKenna, R. A. Panettieri Jr., and S. A. Shore Effect of IL-1beta on CRE-dependent gene expression in human airway smooth muscle cells Am J Physiol Lung Cell Mol Physiol, December 1, 2002; 283(6): L1239 - L1246. [Abstract] [Full Text] [PDF]

				A. J. Ammit, A. L. Lazaar, C. Irani, G. M. O'Neill, N. D. Gordon, Y. Amrani, R. B. Penn, and R. A. Panettieri Jr. 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., April 1, 2002; 26(4): 465 - 474. [Abstract] [Full Text] [PDF]

				S. Page, A. J. Ammit, J. L. Black, and C. L. Armour Human mast cell and airway smooth muscle cell interactions: implications for asthma Am J Physiol Lung Cell Mol Physiol, December 1, 2001; 281(6): L1313 - L1323. [Abstract] [Full Text] [PDF]

				Y. Amrani, A. J. Ammit, and R. A. Panettieri Jr. 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., October 1, 2001; 60(4): 646 - 655. [Abstract] [Full Text] [PDF]