Objective: Proinflammatory cytokines are involved in the pathogenesis of non-thyroidal illness (NTI), its shown by studies with IL-6(-/-) and IL-12(-/-) mice. Interleukin (IL)-6 changes peripheral thyroid hormone metabolism, and IL-12 seems to be involved in the regulation of the central part of the hypothalamic-pituitary-thyroid (HPT) axis during illness. IL-18 is a proinflammatory cytokine which shares important biological properties with IL-12, such as interferon (IFN)-gamma-inducing activity. Design: By studying the changes in the HPT axis during bacterial lipopolysaccharide (LPS)-induced illness in IL-18(-/-), IFNgammaR(-/-) and wild-type (WT) mice, we wanted to unravel the putative role of IL-18 and IFNgamma in the pathogenesis of NTI. Results: LPS induced a decrease in pituitary type 1 deiodinase (D1) activity (P