TY - JOUR
T1 - Tumor necrosis factor-α-induced secretion of RANTES and interleukin-6 from human airway smooth-muscle cells modulation by cyclic adenosine monophosphate
AU - Ammit, A. J.
AU - Hoffman, R. K.
AU - Amrani, Y.
AU - Lazaar, A. L.
AU - Hay, D. W.P.
AU - Torphy, T. J.
AU - Penn, R. B.
AU - Panettieri, Jr
PY - 2000
Y1 - 2000
N2 - 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.
AB - 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.
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U2 - 10.1165/ajrcmb.23.6.4184
DO - 10.1165/ajrcmb.23.6.4184
M3 - Article
C2 - 11104733
AN - SCOPUS:0034530199
SN - 1044-1549
VL - 23
SP - 794
EP - 802
JO - American journal of respiratory cell and molecular biology
JF - American journal of respiratory cell and molecular biology
IS - 6
ER -