In 1994, Mizuhara et al. [] reported no major role of IL-1β in determining ConA-induced hepatitis severity. Accordingly, we observed no significant difference in plasma alanine aminotransferase (ALT) levels, disease incidence, and severity of hepatic necrosis between WT and constitutive IL-1Ra-deficient mice 24 h after ConA injection, suggesting indeed no obvious role of the IL-1/IL-1Ra balance in the initiation of hepatitis (Supporting Information Fig. 5). However, the results described above concerning the production, localization, and cellular source of hepatic IL-1Ra during the course of the disease, led us to perform experiments including both WT and IL-1Ra∆H mice in order to define the contribution of IL-1Ra to the resolution of hepatic damages in response to ConA (48 and 120 h after injection). We observed no significant differences concerning ALT plasma levels between WT and IL-1RaΔH mice which in our opinion is consistent with the observation that the peak severity of hepatitis, and thus the release of liver enzymes by dying hepatocytes, is not modulated by IL-1 (Supporting Information Fig. 4B). However, higher disease incidence and more severe hepatic necrosis were observed in IL-1RaΔH as compared with WT mice 48 h after injection (Fig. 5, left panels). Five days after ConA challenge, no remaining hepatic lesions were observed in WT mice, whereas the liver of IL-1RaΔH mice still exhibited necrotic lesions (Fig. 5, right panels). Numbers of Ki67 positive cells in IL-1RaΔH (0.08 ± 0.07 Ki67 stained-hepatocytes/high power field (HPF); 16.4 ± 5.6 Ki67 stained-nonhepatocytes/HPF) and WT livers (0.16 ± 0.15 Ki67 stained-hepatocytes/HPF; 17.4 ± 5.9 Ki67 stained-nonhepatocytes/HPF) were similar at 48 h after ConA administration, indicating that the initial proliferative response was normal in IL-1RaΔH mice. At 120 h after ConA injection, IL-1RaΔH mice displayed significantly increased numbers of Ki67 stained nuclei in hepatocytes and nonhepatocytes in both pericentral and parenchymal hepatic regions (Fig. 6A). At this same time point, increased numbers of infiltrated inflammatory cells, such as T and B lymphocytes, neutrophils, and macrophages, were observed in portal tracts of ConA-treated IL-1RaΔH livers when compared with WT livers (Fig. 6B and Supporting Information Fig. 6). We observed also similar staining profile in inflammatory clusters of WT livers, suggesting that hepatic IL-1Ra deficiency does not affect the composition of the inflammatory infiltrate (data not shown).In contrast, no difference between the two genotypes was observed 48 h after injection (data not shown). Taken together, our results suggest that hepatic IL-1Ra deficiency, which is associated to excessive IL-1 signaling, led to persisting local inflammation and delayed hepatic regeneration.