Sitagliptin and tofacitinib ameliorate adjuvant induced arthritis via modulating the cross talk between JAK/STAT and TLR-4/NF-κB signaling pathways

Aims: Rheumatoid arthritis is an autoimmune systemic disorder causing pain, swelling, stiffness, and disability in various joints. This work was designed to evaluate the effect of sitagliptin and tofacitinib on Janus kinase (JAK)/signaling transducer and activator of transcription (STAT) and toll like receptor (TLR-4)/nuclear factor kappa B (NF-kappa B) signaling pathways in adjuvant induced arthritis in rats. Materials and methods: Severity of arthritis was evaluated and serum was analyzed for inflammatory mediators. The mRNA and protein expression level of the most important members of the two signaling pathways were determined. Lipid profile, transaminases and renal function parameters were assessed. Key findings: Sitagliptin and tofacitinib significantly decreased the level of inflammatory parameters, the mRNA and protein expression level of the members of JAK/STAT and TLR-4/NF-kappa B pathways with more prominent effect of sitagliptin on TLR-4/NF-kappa B pathway and more expected obvious effect of tofacitinib on JAK/STAT pathway. The combination offered additional anti-inflammatory effect by inhibiting the cross talk between these pathways as inhibition of NF-kappa B activation decreased the serum level of IL-6 preventing the activation of STAT-3 in tibiotarsal tissues. Significance: The combination of tofacitinib and sitagliptin normalized serum lipids and blood glucose level which could offer protection against cardiovascular diseases and caused partial reversal of serum transaminases and creatinine levels which can protect against tofacitinb's related hepato and nephrotoxicity. We could conclude that the combination of Sitagliptin with tofacitinib can offer synergistic anti-inflammatory effect and more protective action against side effects of tofacitinib.