Sulfur mustard primes human neutrophils for increased degranulation and stimulates cytokine release via TRPM2/p38 MAPK signaling

• Published in: Toxicology and applied pharmacology Vol. 258; no. 1; pp. 82 - 88
• Main Authors: Ham, Hwa-Yong, Hong, Chang-Won, Lee, Si-Nae, Kwon, Min-Soo, Kim, Yeon-Ja, Song, Dong-Keun
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 2012; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; Biological and medical sciences; BRASSICA; CALCIUM; Calcium - metabolism; Cell Degranulation - drug effects; Chemical and industrial products toxicology. Toxic occupational diseases; Chemical Warfare Agents - toxicity; CONCENTRATION RATIO; Cytokine release; Cytokines - biosynthesis; Dose-Response Relationship, Drug; Gas, fumes; GLOBAL ASPECTS; Humans; INFLAMMATION; INJURIES; LYMPHOKINES; MAP Kinase Signaling System - physiology; Medical sciences; Mustard Gas - toxicity; Neutrophil; NEUTROPHILS; Neutrophils - drug effects; Neutrophils - physiology; p38 MAPK; p38 Mitogen-Activated Protein Kinases - physiology; PHOSPHORYLATION; Priming; RECEPTORS; SULFUR; Sulfur mustard; Toxicology; Transcription Factor RelA - metabolism; TRPM Cation Channels - physiology; TRPM2; TRPM2; Priming; Cytokine release; Neutrophil; p38 MAPK; Sulfur mustard; Human; Toxic gas; Cytokine; Granulocyte; Chemical warfare agent; Signal transduction; Degranulation; p38 Mitogen activated protein kinase; Release
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2011.10.010

Sulfur mustard (2,2′-bis-chloroethyl-sulfide; SM) has been a military threat since the World War I. The emerging threat of bioterrorism makes SM a major threat not only to military but also to civilian world. SM injury elicits an inflammatory response characterized by infiltration of neutrophils. Although SM was reported to prime neutrophils, the mechanism has not been identified yet. In the present study, we investigated the mechanism of SM-induced priming in human neutrophils. SM increased [Ca 2 + ] i in human neutrophils in a concentration-dependent fashion. Transient receptor potential melastatin (TRPM) 2 inhibitors (clotrimazole, econazole and flufenamic acid) and silencing of TRPM2 by shRNA attenuated SM-induced [Ca 2 + ] i increase. SM primed degranulation of azurophil and specific granules in response to activation by fMLP as previously reported. SB203580, an inhibitor of p38 MAPK, inhibited SM-induced priming. Neither PD98057, an ERK inhibitor, nor SP600215, a JNK inhibitor, inhibited SM-induced priming. In addition, SM enhanced phosphorylation of NF-kB p65 and release of TNF-α, interleukin (IL)-6 and IL-8. SB203580 inhibited SM-induced NF-kB phosphorylation and cytokine release. These results suggest the involvement of TRPM2/p38 MAPK pathway in SM-induced priming and cytokines release in neutrophils. ► SM increased [Ca 2 + ] i in human neutrophils through TPRM2-mediated calcium influx. ► SM primed degranulation of azurophil and specific granules. ► SM enhanced p38 MAPK and NF-κB p65 phosphorylation in human neutrophils. ► SM enhanced release of TNF-α, interleukin (IL)-6 and IL-8 from human neutrophils. ► SB203580 inhibited SM-induced priming, NF-κB p65 phosphorylation and cytokine release.