IL-36–Induced Toxicity in Neonatal Mice Involves TNF-α Production by Liver Myeloid Cells

Human and mouse neonates exhibit limited vaccine responses characterized by predominant Th2 and limited Th1 responses. Because IL-36 exerts a synergic adjuvant effect with IL-12, enhancing Th1 polarization in adult (AD) mice, we administered IL-36 beta to neonatal (1-wk old) and AD control mice at the time of immunization with tetanus toxoid adsorbed to aluminum hydroxide (TT/Alum). Unexpectedly, the combination of IL-36 beta with TT/Alum, which was well tolerated in AD mice, proved toxic and even lethal in neonates. This neonatal toxicity was associated with high Il36r mRNA expression in neonatal liver, resulting in increased cytokine production. Liver Il36r mRNA expression decreased with the termination of fetal liver hematopoiesis, and this decrease correlated with a complete protection from TT/Alum/IL-36 beta-induced mortality. The combination of IL-36 beta and TT/Alum induced the rapid production of TNF-alpha and IFN-gamma by liver myeloid and lymphoid cells, respectively. These responses were less marked when IL-36 beta was used alone, with no adverse effect. The toxicity of IL-36 beta + TT/Alum was abrogated by the administration of a neutralizing anti-TNF-alpha Ab, confirming causality. In conclusion, liver myeloid cells in neonatal mice are an important source of proinflammatory cytokines that may lead to TNF-alpha-mediated toxicity and even lethality.