Diseased Thyrocytes Have Aberrant Communication and TNF Receptor Secretion

Autoimmune diseases are a world-wide health concern and are an intense area of investigation. However, one area of research has been largely ignored. This involves the contribution of the target tissue to the disease process. We hypothesized that cell-cell communication is disrupted by lymphocytic infiltration and advancing fibrosis and this disruption results in altered target cell responses to immune components produced at the site of inflammation, including Tumor Necrosis Factor-alpha (TNF- α). We have used thyroiditis as our model of autoimmunity and have documented the development of spontaneous thyroiditis in MRL-lpr/lpr mice. We have found aberrant connexin expression in thyroid tissue from these mice. The abnormal gap junction assembly persisted when the cells were removed from the inflammation site and cultured in vitro. Primary thyrocyte cultures from these mice were also functionally uncoupled, as indicated by decreased Lucifer Yellow dye transfer. This indicated that mechanisms other than physical disruption were influencing intercellular communication in diseased thyrocytes. Protein kinase C (pKC) decreases connexin 43-mediated communication and regulates numerous cellular properties. We found increased pKC activity in diseased thyrocytes. This enhanced pKC activity was found to be responsible for their decreased cell-cell communication. Furthermore, pKC also decreased T4 release from murine thyrocytes and this decrease was partially mediated through the effect of pKC on intercellular communication. TNF- α did not cause cytotoxic damage to the diseased thyrocytes. We did find, however, that the enhanced pKC activity in the diseased thyrocytes caused an increase in soluble TNF- α receptor production. The production of soluble TNF- α receptors was not the result of proteolytic cleavage of the cell-surface receptor. Instead, the diseased thyrocytes may be secreting soluble receptors. We are the first to report this mode of production for soluble TNF- α receptors