Tumor necrosis factor-α-induced secretion of RANTES and interleukin-6 from human airway smooth-muscle cells modulation by cyclic adenosine monophosphate

A. J. Ammit, R. K. Hoffman, Y. Amrani, A. L. Lazaar, D. W.P. Hay, T. J. Torphy, R. B. Penn, Jr Panettieri

Research output: Contribution to journalArticlepeer-review

116 Scopus citations

Abstract

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];) on tumor necrosis factor (TNF)-α-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-α-induced RANTES secretion but increased TNF-α-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-α-induced RANTES. Collectively, these data demonstrate that increasing [cAMP]/in HASM effectively increases IL-6 secretion but reduces RANTES secretion promoted by TNF-α. Reverse transcriptase/polymerase chain reaction and ribonuclease protection assays suggested that these opposite effects of increased [cAMP]; on TNF-α-induced IL-6 and RANTES secretion may occur at the transcriptional level. Accordingly, we examined the effects of TNF-α and cAMP on the regulation of nuclear factor (NF)-κB, a transcription factor known to modulate cytokine synthesis in numerous cell types. Stimulation of HASM cells with TNF-α increased NF-κB DNA-binding activity. However, increased [cAMP], in HASM neither activated NF-κB nor altered TNF-α-induced NF-κB DNA-binding activity. These results were confirmed using a NF-κB-luciferase reporter assay. Together, our data suggest that TNF-α-induced IL-6 and RANTES secretion may be associated with NF-κB activation, and that inhibition of TNF-α-stimulated RANTES secretion and augmentation of IL-6 secretion by increased [cAMP], in HASM cells occurs via an NF-κB-independent mechanism.

Original languageEnglish (US)
Pages (from-to)794-802
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume23
Issue number6
DOIs
StatePublished - 2000

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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