Sulfur mustard primes human neutrophils for increased degranulation and stimulates cytokine release via TRPM2/p38 MAPK signaling.
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.
Department of Pharmacology, Infectious Diseases Medical Research Center, College of Medicine, Hallym University, Chuncheon, Republic of Korea.
Hwa-Yong
HY
Ham
Chang-Won
CW
Hong
Si-Nae
SN
Lee
Min-Soo
MS
Kwon
Yeon-Ja
YJ
Kim
Dong-Keun
DK
Song
D002118:Calcium / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects*; D002619:Chemical Warfare Agents / Q000633:toxicity*; D016207:Cytokines / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D009151:Mustard Gas / Q000633:toxicity*; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D010766:Phosphorylation; D050053:TRPM Cation Channels / Q000502:physiology; D051996:Transcription Factor RelA / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D002619:Chemical Warfare Agents; D016207:Cytokines; D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; D051996:Transcription Factor RelA; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium; D009151:Mustard Gas