A proinflammatory chemokine, CCL3, sensitizes the heat-gated and capsaicin-gated ion channel, TRPV1

作     者：N Zhang R Sun J Wang JJ Oppenheim S Inan A Cowan TJ Rogers AD Guler M Caterina 

作者机构：Laboratory of Molecular Immunoregulation Intramural Research Support Program Frederick Maryland USA Department of Pharmacology Fels Institute for Cancer Research and Molecular Biology Center for Substance Abuse Research Temple University School of Medicine Philadelphia Pennsylvania USA Department of Biological Chemistry and Department of Neuroscience The Johns Hopkins University School of Medicine Baltimore Maryland USA 

出 版 物：《Arthritis Research & Therapy》 (关节炎研究与治疗)

年 卷 期：2004年第6卷第3期

页      面：1-41页

学科分类：1002[医学-临床医学] 100210[医学-外科学(含：普外、骨外、泌尿外、胸心外、神外、整形、烧伤、野战外)] 10[医学] 

主　　题：Dorsal Root Ganglion Capsaicin Pertussis Dorsal Root Ganglion Neuron U73122 

摘      要：Pain, a critical component of host defense, is one of the hallmarks of the inflammatory response. We therefore hypothesized that pain might be exacerbated by proinflammatory chemokines. To test this hypothesis, CCR1 was co-transfected into HEK293 cells together with the Vanilloid Receptor 1 (TRPV1), a cation channel required for certain types of thermal hyperalgesia. Capsaicin induced calcium influx by TRPV1. When CCR1:TRPV1/HEK293 cells were pretreated with CCL3, the sensitivity of TRPV1-mediated calcium flux was increased about fivefold. Pertusis toxin inhibited CCL3-elicited sensitization of TRPV1, indicating the involvement of G-protein signaling. RT-PCR analysis data showed that a spectrum of chemokine and cytokine receptors are expressed in rat dorsal root ganglia (DRG). Immunohistochemical staining of the DRG showed that CCR1 coexpressed with TRPV1 on over 85% of small diameter neurons. CCR1 on neuronal cells was functional, as demonstrated by CCL3-induced calcium flux and protein kinase C activation. Pretreatment with CCL3 enhanced the response of DRG neurons to capsaicin, and this sensitization was inhibited by pertussis toxin, {type:entrez-nucleotide,attrs:{text:U73122,term_id:4098075}}U73122, or staurosporine. Futhermore, injection of CCL3 into mice spine cords enhances the sensitivity of the mice tails toward the hot water, indicative of chemokine-induced sensitization effects in vivo. The fact that a proinflammatory chemokine, by interacting with its receptor on small-diameter neurons, sensitizes TRPV1 reveals a novel mechanism of receptor cross-sensitization that may contribute to hyperalgesia during inflammation.