Toll-Like Receptor Blockage by TIP-1 and MIP-2 Treatment Mitigates Inflammation in a Mouse Model of Adult-Onset Still's Disease or Still's Disease

Abstract

The inflammatory response triggered by Toll-like receptors (TLRs) may implicated in the development of the pathogenesis of adult-onset Still's disease (AOSD). This study evaluated the efficacy of TLR inhibitor peptides, specifically TLR inhibitor peptide 1 (TIP-1) and MAL/MyD88 inhibitory peptide 2 (MIP-2) in animal models of AOSD. THP-1 cells were stimulated with TLR agonists and treated with TIP-1 or MIP-2. Interferon (IFN)-gamma knock-out mice were induced with AOSD-like symptoms using Mycobacterium mixed with Freund's complete adjuvant (CFA), then treated with the peptides. THP-1 cells treated with TIP-1 and MIP-2 showed significantly decreased expression of TLRs agonist-induced MyD88 and phosphorylated NF-kappaB, except TLR9 agonists. Furthermore, the peptides resulted in a significant decrease in the concentrations of interleukin (IL)-1beta and IL-6 in the culture supernatants, except TLR9 agonists. In animal models of AOSD, treatment with inhibitor peptides significantly improved their clinical symptoms. The administration of these peptides resulted in a significant decrease in serum levels of IL-1beta and IL-18. The expression of inflammatory cytokines were downregulated in the spleen and lymph node of TIP-1 and MIP-2 treated mice. These findings suggest that TIP-1 and MIP-2 may be effective candidates for AOSD treatment, as they have broad specificity for TLRs.