A proinflammatory chemokine, CCL3, sensitizes the heat- and capsaicin-gated ion channel TRPV1.
Pain, a critical component of host defense, is one hallmark of the inflammatory response. We therefore hypothesized that pain might be exacerbated by proinflammatory chemokines. To test this hypothesis, CCR1 was cotransfected into human embryonic kidney (HEK)293 cells together with transient receptor potential vanilloid 1 (TRPV1), a cation channel required for certain types of thermal hyperalgesia. In these cells, capsaicin and anandamide induced Ca(2+) influx mediated by TRPV1. When CCR1:TRPV1/HEK293 cells were pretreated with CCL3, the sensitivity of TRPV1, as indicated by the Ca(2+) influx, was increased approximately 3-fold. RT-PCR analysis showed that a spectrum of chemokine and cytokine receptors is expressed in rat dorsal root ganglia (DRG). Immunohistochemical staining of DRG showed that CCR1 is coexpressed with TRPV1 in >85% of small-diameter neurons. CCR1 on DRG neurons was functional, as demonstrated by CCL3-induced Ca(2+) ion influx and PKC activation. Pretreatment with CCL3 enhanced the response of DRG neurons to capsaicin or anandamide. This sensitization was inhibited by pertussis toxin, U73122, or chelerythrine chloride, inhibitors of Gi-protein, phospholipase C, and protein kinase C, respectively. Intraplantar injection of mice with CCL3 decreased their hot-plate response latency. That a proinflammatory chemokine, by interacting with its receptor on small-diameter neurons, sensitizes TRPV1 reveals a previously undescribed mechanism of receptor cross-sensitization that may contribute to hyperalgesia during inflammation.
Zhang
Ning
N
Laboratory of Molecular Immunoregulation, Intramural Research Support Program, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Frederick, MD 21702-1201, USA.
Inan
Saadet
S
Inan
Sadeet
S
Cowan
Alan
A
Sun
Ronghua
R
Wang
Ji Ming
JM
Rogers
Thomas J
TJ
Caterina
Michael
M
Oppenheim
Joost J
JJ
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D063388:Endocannabinoids; D005727:Ganglia, Spinal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006930:Hyperalgesia / Q000209:etiology / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D007473:Ion Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D053284:Polyunsaturated Alkamides; D051381:Rats; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels; D014162:Transfection
D001095:Arachidonic Acids; C515300:CCR1 protein, human; C515301:Ccr1 protein, mouse; C515302:Ccr1 protein, rat; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D063388:Endocannabinoids; D018836:Inflammation Mediators; D007473:Ion Channels; D019402:Macrophage Inflammatory Proteins; D053284:Polyunsaturated Alkamides; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D002211:Capsaicin; C078814:anandamide