Role And Possible Mechanisms Of Resistin And HMGB1 In Guillain-Barré Syndrome

ObjectivesGuillain-Barré syndrome(GBS)is an immune-mediated polyneuropathy.It has been identified that interactions between cytokines played a key role in the pathogenesis of GBS.Resistin is a proinflammatory cytokine that is involved in the immuneresponse and inflammatory process in various autoimmune diseases via production of cytokines.HMGB1 is actively secreted extracellularly from stimulated macrophages and play a key role in the pathogenesis of neuroinflammation and immune responses.The function of resistin is similar to HMGB1.However,the role of resistin and HMGB1 in patients with GBS has not been reported.Therefore,the aim of this study was to investigate whether GBS-related inflammation could be mediated by resistin via the regulation of HMGB1 and interactions among many downstream cytokines.MethodsWe enrolled 51 patients with GBS and 49 healthy control subjects.Serum levels of resistin,HMGB1,IL-6,and TNF-? were detected using a human resistin enzyme-linked immunosorbent assay(ELISA)kit.We further analyzed associations between serum resistin levels and GBS disability score(GDS)or Erasmus GBS outcome score(EGOS),and associations between serum resistin levels and HMGB1,or IL-6,or TNF-? in these patients.The levels of HMGB1,TNF-?,IL-1?,and IL-6 in the culture medium from THP-1 cells treated with resistin were measured using commercially available ELISA kits.The expression of HMGB1 m RNA and protein in THP-1 cells was determined by real time PCR or western blotting assays.We analyzed expression of the TLR4,p38 MAPK and NF-?B protein in THP-1 cells by western blotting.The levels of HMGB1,TNF-?,IL-1?,and IL-6 in the culture medium from THP-1 cells treated with resistin and inhibitors of p38 MAPK and NF-?B were measured using commercially available ELISA kits.ResultsA significant increase in serum resistin and HMGB1 levels was found in GBS patients compared to healthy controls(p?0.001).There was a significant positive correlation between serum resistin levels and HMGB1 in patients with GBS(r=0.297,p=0.034).We also found that serum resistin levels were positively correlated with IL-6 levels in GBS patients(r=0.297,p=0.035).No significant correlation was found between serum resistin levels and TNF-?(r=-0.016,p=0.908).The results showed that the secretion of HMGB1 in the culture medium from THP-1 cells was increased significantly following treatment with 50ng/m L or 100ng/m L(p<0.05).The levels of IL-1? and IL-6 were both significantly higher in the different resistin treatment groups compared to the blank control group(p?0.05).There was no difference in the TNF-? level between the resistin and blank control groups.The results showed that HMGB1 m RNA and protein levels were increased following treatment with 50 ng/m L or 100 ng/m L(p<0.05).Moreover,TLR4 m RNA and protein levels were increased following treatment with resistin(p<0.05).Compared to the blank control group,THP-1 cells treated with resistin exhibited significant increases in the expression of p38 MAPK and NF-?B(p<0.05).Inhibitors of p38 MAPK and NF-?B significantly decreased the secretion of HMGB1,TNF-?,IL-1?,and IL-6 into the culture medium(p<0.05).Western blotting also revealed that expression of the HMGB1 protein was decreased by these inhibitors(p<0.05).Conclusions1.Elevated serum resistin levels correlate with HMGB1 levels in patients with GBS and may be involved in the pathogenesis of GBS through cytokine interactions.2.Resistin can induce the release of HMGB1,IL-1?,and IL-6,and promotes the synthesis of HMGB1 in THP1 cells.3.Resistin can induce the release of HMGB1,IL-1?,and IL-6,and promotes the synthesis of HMGB1 through TLR4 by activating the NF-?B/MAPK signaling pathway.4.Resistin might be involved in the immunopathological process of GBS through the regulation of HMGB1 and interactions among related downstream cytokines.