J Immunol. 2026 Apr 15;215(4):vkag057. doi: 10.1093/jimmun/vkag057.
ABSTRACT
Chronic antibody-mediated kidney rejection (CABMR) is a major cause of chronic allograft injury. Fibroblasts have been implicated in mediating this injury through activation of the IL-6 amplifier loop (IL-6 + IL-17), driven by the NF-κB and STAT3 signaling pathways. This study investigated the activation of the IL-6 amplifier loop in fibroblasts isolated from renal biopsies of patients with CABMR and evaluated the effects of IL-6 and IL-17 inhibition. Fibroblasts were cultured from 6 CABMR patient biopsy samples and treated with anti-IL-6 (100 ng/mL) and anti-IL-17 (0.75 µg/mL), both before and after stimulation with IL-6/soluble IL-6 receptor (sIL-6R) (20 ng/µL), IL-17 (50 ng/µL), or a combination. IL-6, CCL2, and CCL20 levels were measured in the culture supernatants by ELISA. The mRNA expression of IL-6, CCL2, CCL20, and SOCS3 was assessed using qPCR, and protein expression was evaluated by western blot for phosphorylated STAT3 and NF-κB p65. Synergistic activation of IL-6/sIL-6R and IL-17 significantly increased IL-6, CCL20, and MCP-1 production, whereas SOCS3 expression was downregulated. Phosphorylation of NF-κB and STAT3 was also elevated. The combined inhibition of IL-6 and IL-17 effectively reduced IL-6, MCP-1, and CCL20 levels, restored SOCS3 expression, and attenuated NF-κB and STAT3 phosphorylation. These findings highlight the role of the IL-6 amplifier loop as a potential therapeutic target in CABMR.
PMID:42035495 | DOI:10.1093/jimmun/vkag057