Inhibition of gap junctions relieves the hepatotoxicity of TNF-α.

The aim of this study was to observe the influence of gap junction (GJ) functional changes on the hepatotoxicity of TNF-α. Three different methods were employed to study functional effects of the GJ inhibition: 1) pretreatment with a GJ inhibitor; 2) inoculation of cells at high and low densities; and 3) inhibition of the expression of connexin 32 (Cx32) by small inhibitory RNA transfection. We then observed the influence of these treatments on hepatotoxicity following treatment with different concentrations of TNF-α for various duration. The hepatotoxicity of TNF-α was observed to occur in a dose- and time-dependent manner; after pretreatment inhibition, the hepatotoxicity of TNF-α was significantly reduced (P < 0.01). The hepatotoxicity of TNF-α was also found to be remarkably lower in cells that had been inoculated at low density (as measured by the amount of GJ formation among cells) than in those inoculated at density (P < 0.01). In addition, following Cx32 inhibition, the hepatotoxicity of TNF-α was significantly decreased (P < 0.01) as well. Together, these results suggest that inhibition of GJ function or of its component Cx32 significantly decreases the hepatotoxicity of TNF-α, and that the expression of Cx32 plays an important role in the hepatotoxicity of TNF-α.

[1]  Robert N. Taylor,et al.  Retinoic acid regulates gap junction intercellular communication in human endometrial stromal cells through modulation of the phosphorylation status of connexin 43 , 2013, Journal of cellular physiology.

[2]  C. Cheng,et al.  Connexin 43 is critical to maintain the homeostasis of the blood–testis barrier via its effects on tight junction reassembly , 2010, Proceedings of the National Academy of Sciences.

[3]  A. Harris,et al.  Tramadol and Flurbiprofen Depress the Cytotoxicity of Cisplatin via Their Effects on Gap Junctions , 2009, Clinical Cancer Research.

[4]  Luc Leybaert,et al.  The gap junction cellular internet: connexin hemichannels enter the signalling limelight. , 2006, The Biochemical journal.

[5]  P. Carlen,et al.  General Anesthetics Inhibit Gap Junction Communication in Cultured Organotypic Hippocampal Slices , 2006, Anesthesia and analgesia.

[6]  C. Naus,et al.  General anesthetics attenuate gap junction coupling in P19 cell line , 2005, Journal of neuroscience research.

[7]  Wafaa A. ElSayed,et al.  Tetracycline-regulated expression enables purification and functional analysis of recombinant connexin channels from mammalian cells. , 2004, The Biochemical journal.

[8]  P. Glazer,et al.  Cell-interdependent cisplatin killing by Ku/DNA-dependent protein kinase signaling transduced through gap junctions. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[9]  H. Grossman,et al.  Connexin 26 induces growth suppression, apoptosis and increased efficacy of doxorubicin in prostate cancer cells. , 2004, Oncology reports.

[10]  V. Verselis,et al.  Connexins and apoptotic transformation. , 2003, Biochemical pharmacology.

[11]  A. Boynton,et al.  Connexin 43 (cx43) enhances chemotherapy‐induced apoptosis in human glioblastoma cells , 2001, International journal of cancer.

[12]  K. Kinzler,et al.  A model for p53-induced apoptosis , 1997, Nature.

[13]  H. Imanishi,et al.  Tumor necrosis factor alpha alters the cytotoxic effect of hydrogen peroxide in cultured hepatocytes. , 1997, Biochemical and biophysical research communications.

[14]  D. Remick,et al.  Hepatic ischemia/reperfusion injury: importance of oxidant/tumor necrosis factor interactions. , 1994, The American journal of physiology.

[15]  M. Leist,et al.  Murine hepatocyte apoptosis induced in vitro and in vivo by TNF-alpha requires transcriptional arrest. , 1994, Journal of immunology.

[16]  L. Toledo-Pereyra,et al.  Interleukin 1 and tumor necrosis factor production as the initial stimulants of liver ischemia and reperfusion injury. , 1994, The Journal of surgical research.

[17]  J. Gamble,et al.  Stimulation of neutrophils by tumor necrosis factor. , 1986, Journal of immunology.