Potentiation of tumor necrosis factor-α expression by YC-1 in alveolar macrophages through a cyclic GMP-independent pathway
Journal
Biochemical Pharmacology
Journal Volume
66
Journal Issue
1
Pages
149-156
Date Issued
2003
Author(s)
Abstract
Using cultured rat alveolar NR 8383 macrophages, this study investigated the effect of YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole], a soluble guanylyl cyclase (sGC) activator, on the production of tumor necrosis factor-alpha (TNF alpha). YC-1 enhanced lipopolysaccharide and interferon-gamma (LPS/IFN gamma)-induced TNF alpha formation in a concentration- and time-dependent fashion. YC-1 also caused an increasing effect on the TNF alpha mRNA level, suggesting that the transcriptional process was involved. However, further studies suggested that cyclic GMP did not mediate the potentiation of YC-1 on TNF alpha release, because (a) the sGC inhibitor and the protein kinase G inhibitor failed to block the effect; and (b) the cyclic GMP analogues, on the contrary, concentration-dependently diminished LPS/IFN gamma-induced TNF alpha synthesis. In agreement with this finding, YC-1 produced changes in cell function but no changes in cyclic GMP and cyclic AMP levels or sGC activity. Pretreatment of the cells with cyclooxygenase inhibitors, a p38 mitogen-activated protein kinase inhibitor, a mitogen-activated protein kinase kinase (MEK) inhibitor, and a tyrosine kinase inhibitor did not attenuate the potentiation of TNF alpha release by YC-1. Cycloheximide prevented the YC-1-enhanced TNF alpha formation, implying that new protein synthesis was required. Interestingly, protein kinase C inhibitors enhanced the potentiation of YC-1 to a greater extent. Nevertheless, a protein kinase C activator, phorbol 12-myristate 13-acetate, failed to suppress the potentiation of TNFalpha production by YC-1. In summary, potentiation of TNF alpha release by YC-1 in LPS/IFN gamma-activated alveolar macrophages is an additional mode of action of this compound that is independent of the elevation of cyclic GMP. Thus, caution needs to be used in attributing the YC-1-mediated response to the activation of sGC.
Type
journal article