ELEVATION OF PROTEIN-KINASE-C IN THYROCYTES ISOLATED FROM A LEWIS RATMODEL OF AUTOIMMUNE-THYROIDITIS PREVENTS ASSEMBLY OF IMMUNODETECTABLECONNEXIN43 GAP-JUNCTIONS AND REDUCES INTERCELLULAR COMMUNICATION

In the Lewis rat model of experimental autoimmune thyroiditis (EAT), d ecreased immunodetectable connexin assembly into gap junctions and dim inished intercellular communication are associated with the loss of th yroid function (hypothyroidism) that occurs prior to significant tissu e destruction. The current study explores the hypothesis that the loss of connexin 43 (Cx43)-mediated intercellular communication in these c ells is caused by upregulation of protein kinase C (pKC) activity. Thy rocytes isolated from EAT rats exhibited a 78% increase in basal pKC a ctivity; whereas, basal protein kinase A (pKA) activity was unchanged. Increased pKC activity was a result of increased isozyme protein leve ls. Thyroid cells expressed pKC isozymes gamma and lambda and had elev ated levels of alpha (40%), beta (30%), delta (31%), and epsilon (25%) as quantified by western blot analyses. Furthermore, modulation of pK C activity inversely altered Cx43 assembly and function in monolayer t hyrocytes. For example, octoacetyl glycerol (OAG) treatment of normal thyrocyte monolayers to increase pKC activity resulted in deficient Cx 43 gap junction assembly and reduced intercellular communication indis tinguishable from the deficits in EAT thyrocytes. Conversely, calphost in C inhibition of pKC activity in EAT thyrocyte monolayers restored t hese parameters to normal. Thus, pharmacological modulations of pKC ac tivity in cultured thyrocytes support a causal relation between the ch anges in pKC activity and Cx43-mediated intercellular communication. A bnormalities in autoimmune diseased thyroid tissue (eg, increased pKC) appear to contribute to reduced intercellular coordination of thyroid follicles and thereby can affect subsequent thyroid function. The per sistence of target cell abnormalities in the absence of infiltrating l ymphocytes and their products supports an alternative mechanism by whi ch thyroid function can be affected that does not depend on the loss o f thyroid glandular epithelium.