Role of interleukin‐1β and tumour necrosis factor‐α in lipopolysaccharide‐induced sickness behaviour: a study with interleukin‐1 type I receptor‐deficient mice

Abstract

AbstractInterleukin‐1 (IL‐1) mediates symptoms of sickness during the host response to infection. IL‐1 exerts its effects via several subtypes of receptors. To assess the role of IL‐1 receptor type I (IL‐1RI) in the sickness‐inducing effects of IL‐1, IL‐1β and the cytokine inducer lipopolysaccharide were administered to IL‐1RI‐deficient mice (IL‐1RI–/–). Sickness was assessed by depression of social exploration, anorexia, immobility and body weight loss. IL‐1RI–/– mice were resistant to the sickness‐inducing effects of IL‐1β administered intraperitoneally (2 µg/mouse) and intracerebroventricularly (2 ng/mouse), but still fully responsive to lipopolysaccharide administered intraperitoneally (2.5 µg/mouse) and intracerebroventricularly (3 ng/mouse). The sensitivity of IL‐1RI–/– mice to lipopolysaccharide was not due to a higher brain expression of proinflammatory cytokines other than IL‐1, since lipopolysaccharide‐induced expression of brain IL‐1 β, tumour necrosis factor‐α (TNF‐α) and IL‐6 transcripts were identical in IL‐1RI–/– and control mice when measured by semiquantitative reverse‐transcriptase polymerase chain reaction 1 h after treatment. Blockade of TNF‐α action in the brain by intracerebroventricular administration of a fragment of the soluble TNF receptor, TNF binding protein (3.6 µg/mouse), attenuated the depressive effects of intraperitoneal injection of lipopolysaccharide (1 µg/mouse) on behaviour in IL‐1RI–/– but not in control mice. Since IL‐1RI–/– mice were not more sensitive to intracerebroventricularly TNF‐α (50 ng) than control mice, these results indicate that IL‐1RI mediates the sickness effect of IL‐1 and that TNF‐α simply replaces IL‐1 when this last cytokine is deficient.