Anti-TNF-α monoclonal antibody reverses psoriasis through dual inhibition of inflammation and angiogenesis.

Abstract

Tumor necrosis factor-alpha (TNF-α) antagonists have shown remarkable efficacy in psoriasis; however, the precise mechanisms of action of TNF-α blocking agents mainly focus on their neutralizing TNF-α and its anti-inflammatory effects. In this study, we generated a humanized anti-TNF-α monoclonal antibody (IBI303) and suggested a potential mechanism of anti-TNF-α therapy for psoriasis. The results of SPR and ELISA indicated that IBI303 has a good affinity to TNF-α. In vitro, it could suppress TNF-α-induced cytotoxicity in WEHI164 cells. In vivo, administration of IBI303 to K14-VEGF transgenic mice led to a significant treatment efficiency in psoriasis in a dose-dependent manner. IHC staining and cytokines-ELISA indicated that TNF-α inhibition strongly reduced inflammatory cells infiltration and pro-inflammatory cytokines release, accompanied by suppression of inflamed dermal blood vessels. Mechanistically, in order to explain the anti-angiogenesis effect of anti-TNF-α antibody, the production of cytokine in macrophage conditional medium was measured by ELISA. The result indicated that the massive secretion of TNF-α stimulated by LPS in RAW264.7 cell supernatant was markedly neutralized in a dose-response manner by IBI303, moreover, the expression of NF-κB p65 was down-regulated. Mouse endothelial cell tube formation assay showed that anti-TNF-α could inhibit blood vessels formation directly and indirectly. Collectively, our study suggested a kind of antipsoriatic mechanism of TNF-α inhibitors that is the dual inhibition of inflammation and angiogenesis.

• Authors: Yu Liu, Guoyou Yang, Junfeng Zhang, Kaiyan Xing, Lei Dai, Lin Cheng, Junli Liu, Jie Deng, Gang Shi, Chunlei Li, Xiaolan Su, Shuang Zhang, Yang Yang, Jia Li, Dechao Yu, Rong Xiang, Yuquan Wei, Hongxin Deng
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 28 Issue 1 Pg. 731-43 (Sep 2015) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 26263167 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015. Published by Elsevier B.V.

Chemical References

• Angiogenesis Inhibitors
• Anti-Inflammatory Agents
• Antibodies, Monoclonal, Humanized
• Cytokines
• Tumor Necrosis Factor-alpha
• Vascular Endothelial Growth Factor A

Topics

• Angiogenesis Inhibitors (administration & dosage, therapeutic use)
• Animals
• Anti-Inflammatory Agents (administration & dosage, therapeutic use)
• Antibodies, Monoclonal, Humanized (administration & dosage, therapeutic use)
• Cell Culture Techniques
• Cell Line, Tumor
• Cytokines (immunology, metabolism)
• Macrophages (drug effects, immunology)
• Mice, Transgenic
• Neovascularization, Physiologic (drug effects, immunology)
• Psoriasis (drug therapy, immunology)
• Skin (blood supply, drug effects, immunology)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, immunology)
• Vascular Endothelial Growth Factor A (genetics)