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The effect of tumor necrosis factor-α and cAMP on induction of AP-1 activity in MA-10 tumor leydig cells

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Abstract

The immunostimulant tumor necrosis factor-α (TNFα), produced by monocytes/macrophages in response to inflammatory disorders, regulates gene expression in part through induction of mitogen-activated protein kinases (MAPKs), including the stress-activated protein kinase (SAPK) (c-JunN-terminal kinase [JNK]) and the extracellular signal-regulated kinases (ERKs). In testicular Leydig cells, the induction of steroidogenesis by cAMP is inhibited by TNFα. To examine the potential mechanisms governing the mutual inhibition between cAMP and TNFα in Leydig cells, the intracellular signaling pathways that contribute to AP-1 dependent gene expression were examined in the mouse MA-10 Leydig cell line. TNFα induced SAPK activity sixfold at 15 min, and the PKC inhibitor calphostin C reduced the induction of SAPK by 30%. cAMP induced SAPK activity twofold but reduced TNFα-induced SAPK activity. ERK activity was inhibited by both cAMP and TNFa. TNFa increased c-Jun protein, but only weakly induced FOS proteins (c-Fos, FosB, Fra-1, and Fra-2) whereas cAMP increased the abundance of several FOS proteins (c-Fos, FosB, Fra-1, and Fra-2), with little effect on c-Jun levels. AP-1 binding activity, assessed using electrophoretic mobility shift assays, was increased twofold by TNFα and fivefold by cAMP. Cyclic AMP alone induced AP-1-responsive reporter (p3TPLUX) activity threefold after 2 h with peak effect of 4-fold at 4 hr. AP-1 reporter was not induced by TNFα alone but in the presence of cAMP, TNFα induced AP-1 reporter activity 12-fold. In conclusion, TNFα and cAMP induce distinct components that separately contribute to the modulation of AP-1 activity in MA-10 cells.

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Authors and Affiliations

  1. Department of Physiology and Biophysics (M/C 901), University of Illinois at Chicago, 835 S Wolcott Ave, 60612-7342, Chicago, IL

    Xiangquan Li, Karen Held Hales & Dale Buchanan Hales

  2. The Albert Einstein Cancer Center, Department of Medicine and Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Golding 102, 1300 Morris Park Ave, Bronx, New York

    Genichi Watanabe, Richard J. Lee & Richard G. Pestell

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  1. Xiangquan Li
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  2. Karen Held Hales
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Correspondence to Karen Held Hales.

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Li, X., Hales, K.H., Watanabe, G. et al. The effect of tumor necrosis factor-α and cAMP on induction of AP-1 activity in MA-10 tumor leydig cells. Endocr 6, 317–324 (1997). https://doi.org/10.1007/BF02820509

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