Author: Jiang, Donghai ; Zheng, Shusen ; Chen, Ronggao ; Chen, Bingjie ; Jing, Shilei ; Zhou, Lin ; Zhang, Yanpeng ; Hong, Jiawei ; Owusu-Ansah, Kwabena Gyabaah ; Xie, Haiyang

Y-320, a novel immune-modulator, inhibits IL-17 production by CD4⁺ T cells stimulated with IL-15. Its use in autoimmune diseases such as rheumatoid arthritis has been documented. However, no studies have be conducted to evaluate its application in cancer treatment either as mono or combined therapy. This study demonstrated that while Y-320 had little effect on multidrug resistance (MDR) cell lines, it induced remarkable injury to MDR tumor cells when concurrently administered with other chemotherapeutic agents. Concomitant use of Y-320 with a low dose of paclitaxel significantly sensitized MDR tumors by inducing G2/M phase arrest and apoptosis. Further analyses indicated that Y-320 was a substrate of P-glycoprotein (P-gp). It could inhibit P-gp efflux function without altering P-gp expression, and subsequently reverse P-gp mediated drug resistance in MDR cells. The co-administration of Y-320 and paclitaxel suppressed tumor growth remarkably with an inhibition rate of 77.1% compared to 6.5% in the paclitaxel monotherapy group in vivo. This co-treatment did not increase extra complications in MDR tumor xenograft models. Particularly, no significant changes in body weight and hepatorenal serology were observed with the co-treatment. In conclusion, our results confirm that Y-320 is a promising chemotherapy sensitizer for the first time. The co-administration of Y-320 and chemotherapeutic agents might be an effective and low-toxicity chemotherapeutic regime for the MDR tumor patients.

01 Jan 2007·Japanese Journal of Clinical Immunology

A new orally active anti-rheumatic drug targets IL-15 and IL-17

Review

Author: CHIBA, Kenji

Over production of interleukin (IL)-15 and IL-17 was observed in synovial fluids of rheumatoid arthritis (RA) patients. IL-15 activates T cells and induces IL-17 production whereas IL-17 stimulates synoviocytes to release several mediators of inflammation including IL-6, TNF-alpha, IL-8, and CCL2. Thus, it is presumed that IL-15 and IL-17 play important roles in the pathogenesis of RA. Based on these results, we investigated a new anti-rheumatic drug targets IL-15 and IL-17 and found a new pyrazoleanilide derivative, Y-320 that inhibits IL-15-induced IL-17 production by T cells at 10-nM order. Therapeutic treatment with Y-320 (0.3 to 3 mg/kg orally) significantly inhibited the progression of arthritis and joint destruction in type II collagen-induced arthritis (CIA) in DBA/1J mice. Y-320 inhibited the elevation of IL-17 mRNA expression in the joint of CIA mice. Concomitant treatment with Y-320 and anti-mouse TNF-alpha antibody showed a synergistic effect in mouse CIA. Moreover, therapeutic treatment with Y-320 (0.3 and 1 mg/kg orally) ameliorated CIA in cynomolgus monkeys. Our results suggest that Y-320, a small molecule inhibitor for IL-17 production, is a candidate for the new class of orally active anti-rheumatic drug.

Cell Communication and Signaling

Salidroside attenuates HALI via IL-17A-mediated ferroptosis of alveolar epithelial cells by regulating Act1-TRAF6-p38 MAPK pathway

Article

Author: Hu, Zhansheng ; Guo, Baoyue ; Hou, Yang ; Liu, Xuezheng ; Wang, Lulu ; Liang, Zhuang ; Di, Xingwei ; Xu, Bo ; Gong, Gu ; Zuo, Zhongfu ; Zhang, Xiaoyu ; Huang, Ying

AbstractBackground and PurposeHyperoxia-induced acute lung injury (HALI) is a critical life-threatening disorder characterized by severe infiltration immune cells and death of type II alveolar epithelial cells (AECII). However, little is known about the relations between immune cells and AECII in HALI. IL-17A is a pro-inflammatory cytokine mainly secreted by Th17 cells, contributing to the pathogenesis of various inflammatory diseases. The present study investigated the role of IL-17A in cell–cell communication between immune cells and AECII in HALI, and explored the therapeutic effect of salidroside (Sal, a natural anti-inflammatory agents) on HALI.MethodsMice with HALI were induced by exposure to hyperoxia over 90% for 12 h, 24 h, 48 h or 72 h, and the optimal timing was detected by H&E and Masson staining. Ferroptosis was confirmed by detecting the levels of MDA, Fe2+ and GPX4, and the morphological alterations of AECII under transmission electron microscopy. The expression of pro-inflammatory cytokine, including IL-6, TGF-β1, IL-17A and IL-17A receptor (IL-17RA) were measured by Western blotting and immunohistochemical stanning. The ferroptosis-related Act1/TRAF6/p38 MAPK pathway was detected by Western blotting. The role of pro-inflammatory cytokine IL-17A for AECII ferroptosis, and the effect of Sal on HALI were investigated by administration of Y-320 (IL-17 inhibitor) and Sal respectively 3 days before mice exposed to hyperoxia. ResultsMice exposed to hyperoxia for 24 h suffered sufficient HALI with inflammatory cell infiltration and collagen deposition, and exhibited features of ferroptosis under TME. Meanwhile, compared with sham mice, mice exposed to hyperoxia showed down-regulation of GPX4, and up-regulation of IL-6, TGF-β1, IL-17A, IL-17RA, Act1, TRAF6, p38 MAPK and p-p38 MAPK. Moreover, inhibition of IL-17A with Y-320 or administration with Sal could reverse the effect caused by hyperoxia respectively. ConclusionsIL-17A is associated with immune cells infiltration in HALI, and contributes to ferroptosis of AECII that related to Act1/TRAF6/p38 MAPK pathway. Additionally, Sal protects against HALI throughout the whole pathogenic process.

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Indication	Highest Phase	Country/Location	Organization	Date
Rheumatoid Arthritis	Preclinical	JP	Mitsubishi Pharma Corp.	13 Jun 2007

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