TY - JOUR
T1 - Cyclic AMP inhibits production of interleukin-6 and migration in human vascular smooth muscle cells
AU - Newman, Walter H.
AU - Castresana, Manuel R.
AU - Webb, Jerry G.
AU - Wang, Zhongbiao
N1 - Funding Information:
The authors thank Benjamin P. Mitchell for technical assistance. This work was supported by grants from the MedCen Foundation, the Clinical Research Center of the Medical Center of Central Georgia, and the American Heart Association, Mid-Atlantic Affiliate.
PY - 2003/1
Y1 - 2003/1
N2 - Background. Gene expression induced by tumor necrosis factor-α (TNF-α) is involved in the regulation of vascular smooth muscle cell (VSMC) proliferation and migration, two events critical to formation of stenotic vascular lesions. In some systems, elevating adenosine 3′,5′-cyclic monophosphate (cyclic AMP) inhibits TNF-α induced gene transcription. We recently demonstrated that interleukin-6 (IL-6) was chemotactic to VSMC. Therefore, we tested the hypothesis that elevating cyclic AMP would inhibit TNF-α-mediated IL-6 expression and VSMC migration. Materials and methods. VSMC were cultured from saphenous vein remaining after coronary artery bypass grafting. Migration of VSMC through a porous membrane was determined. Intracellular cyclic AMP was elevated by exposing the cells to forskolin or 8-Br-cyclic AMP and was measured by radioimmunoassay. IL-6 was measured by enzyme-linked immunosorbent assay. Results. TNF-α induced migration of VSMC in a concentration-dependent manner. Incubation of cells with forskolin significantly increased cyclic AMP. Co-incubation of cells with TNF-α in combination with 8-Br-cyclic AMP or forskolin inhibited migration by approximately 25 and 70%, respectively. Incubation with TNF-α increased release of IL-6 from VSMC 18-fold over basal. This stimulated release was inhibited by either 8-Br-cyclic AMP or forskolin. In cells stimulated with TNF-α, addition of an antibody to IL-6 reduced migration by 25%. Conclusions. These data show that IL-6 produced by VSMC contributes to cell migration induced by TNF-α. Further, elevating cyclic AMP inhibited TNF-α-induced release of IL-6, and migration of VSMC. These results are consistent with the notion that mechanisms that increase intracellular cyclic AMP, such as activation of β-adrenergic receptors on VSMC, act as a brake on cell migration.
AB - Background. Gene expression induced by tumor necrosis factor-α (TNF-α) is involved in the regulation of vascular smooth muscle cell (VSMC) proliferation and migration, two events critical to formation of stenotic vascular lesions. In some systems, elevating adenosine 3′,5′-cyclic monophosphate (cyclic AMP) inhibits TNF-α induced gene transcription. We recently demonstrated that interleukin-6 (IL-6) was chemotactic to VSMC. Therefore, we tested the hypothesis that elevating cyclic AMP would inhibit TNF-α-mediated IL-6 expression and VSMC migration. Materials and methods. VSMC were cultured from saphenous vein remaining after coronary artery bypass grafting. Migration of VSMC through a porous membrane was determined. Intracellular cyclic AMP was elevated by exposing the cells to forskolin or 8-Br-cyclic AMP and was measured by radioimmunoassay. IL-6 was measured by enzyme-linked immunosorbent assay. Results. TNF-α induced migration of VSMC in a concentration-dependent manner. Incubation of cells with forskolin significantly increased cyclic AMP. Co-incubation of cells with TNF-α in combination with 8-Br-cyclic AMP or forskolin inhibited migration by approximately 25 and 70%, respectively. Incubation with TNF-α increased release of IL-6 from VSMC 18-fold over basal. This stimulated release was inhibited by either 8-Br-cyclic AMP or forskolin. In cells stimulated with TNF-α, addition of an antibody to IL-6 reduced migration by 25%. Conclusions. These data show that IL-6 produced by VSMC contributes to cell migration induced by TNF-α. Further, elevating cyclic AMP inhibited TNF-α-induced release of IL-6, and migration of VSMC. These results are consistent with the notion that mechanisms that increase intracellular cyclic AMP, such as activation of β-adrenergic receptors on VSMC, act as a brake on cell migration.
KW - Cyclic AMP
KW - Interleukin-6
KW - Smooth muscle cell migration, tumor necrosis factor-α
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U2 - 10.1016/S0022-4804(02)00038-0
DO - 10.1016/S0022-4804(02)00038-0
M3 - Article
C2 - 12591236
AN - SCOPUS:0037289168
SN - 0022-4804
VL - 109
SP - 57
EP - 61
JO - Journal of Surgical Research
JF - Journal of Surgical Research
IS - 1
ER -