Research On The Mechanism Of IL1R1 Effect On Mice Liver Injury

As its many physiological functions and unique potential of regenerative,liverhas become the most important metabolic organ inhuman and animals.Liver,also like other organs,is gradually aging,but its function seems to be consaved.Studieshave shown that such a maintained of function is dependent on a unique potential of liver regeneration.Recent years,patients with a acutehepatic failure caused byhepatitis,alcohol and drugshas a significant increased,and because the acute liver failurehas multi etiology,unexceped,many complications and more characteristics,there are no therapymethods and drugs,particularly effective,for acute liver failure,and the older patients suffered ahigh risk for death especially.IL-1 is a widespread inflammatory cytokine in vivo,IL-1 signal is critical in response to the infection and injury of biological.Clearly,the signaling of IL-1has play a key role in the aging liver function maintenance process and repairy procedure after acute liver injury as the above-described.As the major type of IL-1 receptor,IL-1R1 is responsible for mediating almost IL-1's physiological functions.However,the role and the mechanism of IL-1R1have played in mice liver regeneration after liver injuryhas not been studied,especially in the aged mice.In recent years,gene knock-out technologyhas been broadly adhibition to the study of functional genomics,due to it can modify a particular gene so that to devitalization or delete this target gene.So we introduced the IL-1R1 KO mice,and established a liver regeneration model of 2/3 sectionalhepatectomy and a CCl₄-induced acute liver failure model to study the role of IL-1R1 in the recovery process after aging mice liver injury and its pathway in molecular level.The expression of IL-1R1 mRNA immediately increased and reach the peak at 6h after the 2/3 partial liver resection of aging mice,we guess that IL-1R1 may be promote the start of liver regeneration and cell proliferation by mediate IL-1 signal transduction.In order to further study the effects and its mechanism of IL-1R1 plays in liver regeneration,the early inflammatory cytokines TNF-?,Emr1,Mcp-1,IL-6,Ccr2 and Ifn-?,early immediate factors gene Fos and c-Jun,cyclin regulatory genes and proteins Cyclin D1,Cyclin A2,Cyclin B1,proliferation-associated protein PCNA and signaling molecules of proliferation pathways JNK1,NF-?B and STAT3,apoptosis pathway related protein Caspase-8,Caspase-3,Bax and Bcl-2 were detected,the results showed that in the IL-1R1 KO mice,Fos and c-Jun were significantly reduced and delayed in the late liver regeneration;the expression of Cyclin D1 is reduced and latency compared with WT mice,PCNA is delayed;the ratio of phospho-JNK1 is significantly decreased in IL-1R1 KO aged mice,compared to the WT mice;the ratio of phosphor-STAT3 is reducted and delayed in late liver regeneration;the expression of Bax significantly up-regulated after PH 6h,the markable upregulated of Caspase-3 expression is emerge after PH 120h.Overall,aged mice,whice suffed with IL-1R1 KO,has a reduced capacity of liver regeneration after rejection,mainly to suppress or delay the proliferation of liver cells by inhibiting the activation of JNK1 and STAT3 proliferation signal pathway and promotehepatocyte apoptosis by enhancing the expression of Caspase-3 and Bax.After aging mice suffered CCl₄,compared with the Control,the expression of IL-1R1 mRNA is significantly increases in the whole process of CCl₄-induced acute liver failure,indicating that IL-1R1 may play an critical role in acute liver failure.Serum ALT,AST testing and H.E staining results of Hepatic tissue sections showed some differences in IL-1R1 KO mice and WT mice.Subsequently detective about inflammatory cytokine gene Tnf-a,Emr1,Mcp-1,IL-6,Ccr2 and Ifn-?,liver function protein SOD2,PAFAH1B2,and GGT1,apoptosis protein Caspase-8,Caspase-3,Bax and Bcl-2,and GSH showed that,in IL-1R1 KO aged mice,TNF-? and Mcp-1 expression less than WT mice aged at most of the time points,futher the expression of Ifn-?,Ccr2 and Emr1 just belew WT aged mice in a few time spots.The expression of SOD2,PAFAH1B2 is slightly lower than in WT mice.Caspase-8 and Bax significantly up-regulated in a particular time points.GSH content was significantly lower than WT controls 28h after CCl₄ treatment.These results indicate that,IL-1R1 KOhinder the normal function of pro-inflammatory cytokines IL-1 to a certain extent,affecting the timing and extent of inflammatory response,but acute liver failure aged micehave a similar liver injury with WT mice,and changed little overall.