Inflammatory cytokines and type I 5'-deiodinase expression in phi1 rat liver cells

Administration of tumour necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) to animals and humans results in changes in circulating thyroid hormone concentrations similar to those seen in non-thyroidal illness (NTI). Inflammatory cytokines have been postulated as mediators of the euthyroid sick syndrome by inhibiting type 1 5'-deiodinase (5'D-I) enzyme activity. We have investigated direct effects of cytokines upon 5'D-I expression, measuring changes in 5'D-I enzyme activity and mRNA in phi1 rat liver cells. All three cytokines stimulated 5'D-I enzyme activity: TNF alpha 326 +/- 43% (100% in controls, mean + S.E.M., n = 9, P < 0.01 by ANOVA), IL-1beta 297 +/- 8% and IL-6 272 +/- 25%. Co-incubation with cycloheximide abolished stimulation by each cytokine. Kinetic analysis revealed that stimulation of 5'D-I enzyme activity was a result of significantly increased Vmax, (P < 0.01 by ANOVA) with Km relatively unchanged. 5'D-I mRNA abundance was not significantly changed following treatment by any of the three cytokines. These findings do not support the hypothesis that inflammatory cytokines may mediate the euthyroid sick syndrome by causing inhibition of 5'D-I activity.