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

Although 3 9 :5 9 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)a –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) E 2 , forskolin, or dibutyryl cAMP inhibited TNFa –induced RANTES secretion but increased TNFa –induced IL-6 secretion. Moreover, stimulation with PGE 2 , 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 PGE 2 and forskolin on TNFa –induced RANTES. Collectively, these data demonstrate that increasing [cAMP] i in HASM effectively increases IL-6 secretion but reduces RANTES secretion promoted by TNFa . Reverse transcriptase/polymerase chain reaction and ribonuclease protection assays suggested that these opposite effects of increased [cAMP] i on TNFa – induced IL-6 and RANTES secretion may occur at the transcriptional level. Accordingly, we examined the effects of TNFa and cAMP on the regulation of nuclear factor (NF)k B, a transcription factor known to modulate cytokine synthesis in numerous cell types. Stimulation of HASM cells with TNFa increased NFk B DNA-binding activity. However, increased [cAMP] i in HASM neither activated NFk B nor altered TNFa – induced NFk B DNA-binding activity. These results were confirmed using a NFk B–luciferase reporter assay. Together, our data suggest that TNFa –induced IL-6 and RANTES secretion may be associated with NFk B activation, and that inhibition of TNFa –stimulated RANTES secretion and augmentation of IL-6 secretion by increased [cAMP] i in HASM cells occurs via an NFk B–independent mechanism.

[1]  H. Hoogsteden,et al.  Tumor Necrosis Factor-a Enhances mRNA Expression and Secretion of Interleukin-6 in Cultured Human Airway Smooth Muscle Cells , 2000 .

[2]  G. Haegeman,et al.  The Nuclear Factor-κB Engages CBP/p300 and Histone Acetyltransferase Activity for Transcriptional Activation of the Interleukin-6 Gene Promoter* , 1999, The Journal of Biological Chemistry.

[3]  C. Billington,et al.  Inflammatory and contractile agents sensitize specific adenylyl cyclase isoforms in human airway smooth muscle. , 1999, American journal of respiratory cell and molecular biology.

[4]  A. Strosberg,et al.  MHC class II engagement in brain endothelial cells induces protein kinase A-dependent IL-6 secretion and phosphorylation of cAMP response element-binding protein. , 1999, Journal of immunology.

[5]  Z. Zídek.  Adenosine - cyclic AMP pathways and cytokine expression. , 1999, European cytokine network.

[6]  E. Johns,et al.  Modulation of interleukin-6 by beta2-adrenoceptor in endotoxin-stimulated renal macrophage cells. , 1999, Kidney international.

[7]  R. Panettieri,et al.  Dexamethasone Pathway That Is Only Partially Sensitive to B-dependent Signaling Κ Involves an Nf- Human Tracheal Smooth Muscle Cells Up-regulation of Icam-1 by Cytokines In , 2013 .

[8]  B. Luckow,et al.  Transcriptional regulation of the interleukin-6 gene in mesangial cells. , 1999, Journal of the American Society of Nephrology : JASN.

[9]  S. Christensen,et al.  Ariflo (SB 207499), a second generation phosphodiesterase 4 inhibitor for the treatment of asthma and COPD: from concept to clinic. , 1999, Pulmonary pharmacology & therapeutics.

[10]  J. Moy,et al.  Stimulus‐specific regulation of chemokine expression involves differential activation of the redox‐responsive transcription factors AP‐1 and NF‐κB , 1999, Journal of leukocyte biology.

[11]  K. Kubo,et al.  Procaterol inhibits IL-1b- and TNF-a-mediated epithelial cell eosinophil chemotactic activity , 1999 .

[12]  D. H. Lee,et al.  Release of tumor necrosis factor-α from coronary smooth muscle : Activation of NF-κB and inhibition by elevated cyclic AMP , 1998 .

[13]  R. Panettieri.  Cellular and molecular mechanisms regulating airway smooth muscle proliferation and cell adhesion molecule expression. , 1998, American journal of respiratory and critical care medicine.

[14]  E. Puré,et al.  CD40-mediated signal transduction in human airway smooth muscle. , 1998, Journal of immunology.

[15]  J. Benovic,et al.  Mechanisms of acute desensitization of the beta2AR-adenylyl cyclase pathway in human airway smooth muscle. , 1998, American journal of respiratory cell and molecular biology.

[16]  S. Christensen,et al.  1,4‐Cyclohexanecarboxylates: Potent and Selective Inhibitors of Phosphodiesterase 4 for the Treatment of Asthma. , 1998 .

[17]  J. Habener,et al.  Cyclic AMP signaling and gene regulation. , 1998, Annual review of nutrition.

[18]  Yoshihiro Ohmori,et al.  Synergy between Interferon-γ and Tumor Necrosis Factor-α in Transcriptional Activation Is Mediated by Cooperation between Signal Transducer and Activator of Transcription 1 and Nuclear Factor κB* , 1997, The Journal of Biological Chemistry.

[19]  A. Fauci,et al.  Nuclear factor-kappa B potently up-regulates the promoter activity of RANTES, a chemokine that blocks HIV infection. , 1997, Journal of immunology.

[20]  B. Banas,et al.  Regulation of RANTES and ICAM-1 expression in murine mesangial cells. , 1997, Journal of the American Society of Nephrology : JASN.

[21]  K. Chung,et al.  Human airway smooth muscle cells express and release RANTES in response to T helper 1 cytokines: regulation by T helper 2 cytokines and corticosteroids. , 1997, Journal of immunology.

[22]  P. Forsythe,et al.  Increased MCP-1, RANTES, and MIP-1alpha in bronchoalveolar lavage fluid of allergic asthmatic patients. , 1996, American journal of respiratory and critical care medicine.

[23]  T. Hirano,et al.  Triggering of the Human Interleukin-6 Gene by Interferon-γ and Tumor Necrosis Factor-α in Monocytic Cells Involves Cooperation between Interferon Regulatory Factor-1, NFκB, and Sp1 Transcription Factors (*) , 1995, The Journal of Biological Chemistry.

[24]  E. Puré,et al.  T lymphocytes adhere to airway smooth muscle cells via integrins and CD44 and induce smooth muscle cell DNA synthesis , 1994, The Journal of experimental medicine.

[25]  T. Libermann,et al.  Multiple regulatory elements in the interleukin-6 gene mediate induction by prostaglandins, cyclic AMP, and lipopolysaccharide , 1994, Molecular and cellular biology.

[26]  A. Krensky,et al.  Genomic organization and transcriptional regulation of the RANTES chemokine gene. , 1993, Journal of immunology.

[27]  R. Zitnik,et al.  cAMP inhibition of interleukin-1-induced interleukin-6 production by human lung fibroblasts. , 1993, The American journal of physiology.

[28]  D. Broide,et al.  Cytokines in symptomatic asthma airways. , 1992, The Journal of allergy and clinical immunology.

[29]  R. Panettieri,et al.  A human airway smooth muscle cell line that retains physiological responsiveness. , 1989, The American journal of physiology.