THYROXINE ADMINISTRATION PREVENTS STREPTOCOCCAL CELL WALL-INDUCED INFLAMMATORY RESPONSES

Administration of streptococcal cell wall (SCW) preparation induces an inflammatory response in susceptible animals that is a model frequent ly used for rheumatoid arthritis. The degree of inflammation produced by SCW is greatly enhanced by low endogenous levels of glucocorticoids due to diminished hypothalamic-pituitary-adrenal activity. Because de creased glucocorticoid production is known to occur in the hypothyroid state, we tested whether hypothyroidism would increase, and conversel y, whether hyperthyroidism would decrease. the inflammatory responses to SCW. Adult female Sprague Dawley rats were fed a regular diet (cont rol), L-T-4 (T-4; hyperthyroid), or 6-propyl-thiouracil (hypothyroid) in drinking water for 7 weeks. Hypothyroidism resulted in elevated pla sma levels of TSH and hypothalamic preproTRH messenger RNA (mRNA) whil e reducing anterior pituitary POMC mRNA and plasma ACTH and corticoste rone levels. In contrast, hyperthyroid rats produced opposite results: decreased measures of central thyroid function but increased pituitar y-adrenal function. Three days after administration of SCW, macrophage inflammatory protein-1 alpha and interleukin-1 beta mRNA expression i ncreased dramatically in controls and even further in hypothyroid anim als, as measured by Northern blot analysis. In contrast, T-4-treated r ats showed significant inhibition of these inflammatory markers. Thus, the hyperthyroid state combined with increased endogenous glucocortic oid levels is protective against inflammatory challenges. The inverse relationship between preproTRH expression and pituitary-adrenal functi on suggests the possibility of a direct inhibitory link connecting the hypothalamic-pituitary-adrenal and thyroid axes, and suggests alterna tive sites of therapeutic intervention for rheumatoid arthritis and ot her inflammatory associated disorders.