A novel cyclic helix B peptide inhibits dendritic cell maturation during amelioration of acute kidney graft rejection through Jak-2/STAT3/SOCS1

C Yang,M Xu,M Hu,Y Long,J Wang,L Wang,R Rong,L Li,Y Zhang,T Zhu

doi:10.1038/cddis.2015.338

Abstract

We recently synthesized a novel proteolysis-resistant cyclic helix B peptide (CHBP) that exhibits promising renoprotective effects. Dendritic cells (DCs) play an activation role in acute rejection (AR). Thus, the present study was designed to investigate the effects of CHBP on DCs in a rat renal transplantation model. The left kidney was harvested from male Lewis rats and then transplanted into male Wistar rats with or without CHBP treatment. Five successive treatment doses of CHBP after transplantation significantly ameliorated AR with lower histological injury, apoptosis and CD4+ and CD8+ T-cell infiltration in renal allografts. CHBP reduced IFN-γ and IL-1β levels but increased IL-4 and IL-10 levels in the serum. The number of mature DCs was significantly decreased in renal allografts treated with CHBP. In addition, incubating DCs with CHBP in vitro led to reduction in TNF-α, IFN-γ, IL-1β and IL-12 levels and increase of IL-10 expression at the protein level in the supernatant. Mechanistically, CHBP inhibited TLR activation-induced DC maturation by increasing SOCS1 expression through Jak-2/STAT3 signaling. In conclusion, CHBP suppresses renal allograft AR by inhibiting the maturation of DCs via Jak-2/STAT3/SOCS1 signaling, suggesting that CHBP may be an potential therapeutic drug for treating renal AR.

Highlights

For many years, acute rejection (AR) has been considered to be a typical response of the adaptive immune system
Because OX62 is a specific marker of rat dendritic cells (DCs) and major histocompatibility complex (MHC)-II and CD86 are vital for the Ag-presenting function of DCs, decreased numbers of OX62+ cells combined with MHC-II+ or CD86+ positive cells in the cyclic helix B peptide (CHBP)-treated renal allografts indicated that CHBP suppressed mature DC location in the renal allografts (Figure 3b)
We demonstrate for the first time that the novel peptide CHBP ameliorates AR in a rat renal transplantation model

Summary

Introduction

AR has been considered to be a typical response of the adaptive immune system. Recent investigations have revealed a critical role for the innate immune system as a pivotal trigger in adaptive immune responses.[4,5,6,7] During the recovery of an allograft from a donor, the process of recovery leads to the induction of stress in the allograft, including physical factors and ischemia reperfusion injury These injuries caused by organ manipulation induce the expression of damage-associated molecular patterns, such as heat-shock proteins, that are recognized by pattern recognition receptors (PRRs) localized on immune cells such as dendritic cells (DCs).[8] Toll-like receptors (TLRs), which are important and typical PRRs, are activated by these danger signals and alert the DCs through the activation of transcription factors that encode the genes regulating inflammatory cells and mediators. We further clarified that the mechanism underlying the inhibition of TLR-induced DC maturation by CHBP is dependent on the activation of suppressor of cytokine signaling (SOCS) 1

Methods

Results

Conclusion