TMP Attenuates Intraocular Inflammation In Experimental Autoimmune Uveitis Through Modulating STAT3 And STAT4 Pathways

Background: In clinical,uveitis is a diverse group of intraocular inflammatory diseases that mainly generated by infectious or autoimmune responses,and it is a chronic relapsing disease.The recurrent inflammation of uveitis causes retinal impairment and blindness.At present,the autoimmune related form is the major pathogenesis of uveitis.It is important to find the drugs and treatments for uveitis in ophthalmology.Purpose: To investigate the protective effect of TMP against retinal inflammation in experimental autoimmune uveitis(EAU)mice and explore its underlying mechanism.Methods: Mice were subcutaneous injected by IRBP peptide with CFA to induce EAU.TMP(50 mg/kg/d)or vehicle was administrated intraperitoneally starting from day 3 prior to day 14 after IRBP peptide immunization as the prevention phase,and from day 8 to day 14 as the effector phase,respectively.The clinical and histological scores were used to evaluate the severity of ocular inflammation in EAU mouse eyes.The pro-inflammatory cytokines IL-6,TNF-?,IL-1?,MCP-1,anti-inflammatory cytokine IL-10,Th1 cell signature cytokine IFN-? and Th17 cell signature cytokine IL-17 were detected by real-time PCR.Retinal function was assessed by ERG.The protein levels of p-STAT3 and p-STAT4 were detected by Western blotting.Results: In prevention and effector phases,the clinical and histological scores were remarkable reduced in EAU mice treated with TMP systemically.Intraperitoneal administration of TMP significantly decreased the retinal m RNA expression of IL-6,TNF-?,IL-1?,MCP-1,IFN-? and IL-17,but significantly enhanced the expression of IL-10 in EAU.Compared with the vehicle treated EAU groups,the ERG b-and a-wave amplitudes were alleviated in the TMP treated EAU eyes.Meanwhile,TMP significantly preserved the expression of p-STAT3 and p-STAT4 at the protein levels.Conclusion: We found systemic administration of TMP significantly reduced ocular inflammation and retinal function impairment in both prevention and effector phases of EAU.Our results suggested the anti-inflammatory effect of TMP is associated with inhibition of the immune response pathways,including STAT3 and STAT4 signaling.