Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

PNAS 102 (12): 4536-4541

Copyright © 2005 by the National Academy of Sciences.


IMMUNOLOGY

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

Ning Zhang *, Saadet Inan {dagger}, Alan Cowan {dagger}, Ronghua Sun *, Ji Ming Wang *, Thomas J. Rogers {dagger}, Michael Caterina {ddagger}, and Joost J. Oppenheim *, §

*Laboratory of Molecular Immunoregulation, Intramural Research Support Program, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Frederick, MD 21702-1201; {ddagger}Departments of Biological Chemistry and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287; and {dagger}Department of Pharmacology, Fels Institute for Cancer Research and Molecular Biology, Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved February 11, 2005

Received for publication August 17, 2004.

Abstract: 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 Ca2+ influx mediated by TRPV1. When CCR1:TRPV1/HEK293 cells were pretreated with CCL3, the sensitivity of TRPV1, as indicated by the Ca2+ influx, was increased {approx}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 Ca2+ 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.

Key Words: CCR1 • chemokine receptor • inflammation • pain


Author contributions: N.Z., S.I, A.C., R.S., T.J.R., M.C., and J.J.O. designed research; N.Z., S.I., A.C., R.S., J.M.W., T.J.R., and M.C. performed research; N.Z., A.C., J.M.W., T.J.R., M.C, and J.J.O. analyzed data; and N.Z., A.C., T.J.R., M.C., and J.J.O. wrote the paper.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: TRPV1, transient receptor potential vanilloid 1; CAP, capsaicin; DRG, dorsal root ganglia; PLC, phospholipase C; Ana, anandamide; PTX, pertussis toxin.

§ To whom correspondence should be addressed. E-mail: oppenhei{at}ncifcrf.gov.

© 2005 by The National Academy of Sciences of the USA


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Heat shock factor 1 regulates the expression of the TRPV1 gene in the rat preoptic-anterior hypothalamus area during lipopolysaccharide-induced fever.
M. Fan-xin, S. Li-mei, S. Bei, Q. Xin, Y. Yu, and C. Yu (2012)
Exp Physiol 97, 730-740
   Abstract »    Full Text »    PDF »
C-terminal Dimerization Activates the Nociceptive Transduction Channel Transient Receptor Potential Vanilloid 1.
S. Wang and H.-h. Chuang (2011)
J. Biol. Chem. 286, 40601-40607
   Abstract »    Full Text »    PDF »
CXCL5 Mediates UVB Irradiation-Induced Pain.
J. M. Dawes, M. Calvo, J. R. Perkins, K. J. Paterson, H. Kiesewetter, C. Hobbs, T. K. Y. Kaan, C. Orengo, D. L. H. Bennett, and S. B. McMahon (2011)
Science Translational Medicine 3, 90ra60
   Abstract »    Full Text »    PDF »
Painful Pathways Induced by TLR Stimulation of Dorsal Root Ganglion Neurons.
J. Qi, K. Buzas, H. Fan, J. I. Cohen, K. Wang, E. Mont, D. Klinman, J. J. Oppenheim, and O. M. Z. Howard (2011)
J. Immunol. 186, 6417-6426
   Abstract »    Full Text »    PDF »
Distinct Modulations of Human Capsaicin Receptor by Protons and Magnesium through Different Domains.
S. Wang, K. Poon, R. E. Oswald, and H. h. Chuang (2010)
J. Biol. Chem. 285, 11547-11556
   Abstract »    Full Text »    PDF »
Trichostatin A, a histone deacetylase inhibitor, reduces lesion growth and hyperalgesia in experimentally induced endometriosis in mice.
Y. Lu, J. Nie, X. Liu, Y. Zheng, and S.-W. Guo (2010)
Hum. Reprod. 25, 1014-1025
   Abstract »    Full Text »    PDF »
Expression and function of CXCL12/CXCR4 in rat urinary bladder with cyclophosphamide-induced cystitis.
L. Arms, B. M. Girard, and M. A. Vizzard (2010)
Am J Physiol Renal Physiol 298, F589-F600
   Abstract »    Full Text »    PDF »
GRK2: A Novel Cell-Specific Regulator of Severity and Duration of Inflammatory Pain.
N. Eijkelkamp, C. J. Heijnen, H. L. D. M. Willemen, R. Deumens, E. A. J. Joosten, W. Kleibeuker, I. J. M. den Hartog, C. T. J. van Velthoven, C. Nijboer, M. A. Nassar, et al. (2010)
J. Neurosci. 30, 2138-2149
   Abstract »    Full Text »    PDF »
Inhibitor {kappa}B Kinase {beta} Deficiency in Primary Nociceptive Neurons Increases TRP Channel Sensitivity.
V. Bockhart, C. E. Constantin, A. Haussler, N. Wijnvoord, M. Kanngiesser, T. Myrczek, G. Pickert, L. Popp, J.-M. Sobotzik, M. Pasparakis, et al. (2009)
J. Neurosci. 29, 12919-12929
   Abstract »    Full Text »    PDF »
Sustained Morphine Treatment Augments Capsaicin-Evoked Calcitonin Gene-Related Peptide Release from Primary Sensory Neurons in a Protein Kinase A- and Raf-1-Dependent Manner.
S. Tumati, H. I. Yamamura, T. W. Vanderah, W. R. Roeske, and E. V. Varga (2009)
J. Pharmacol. Exp. Ther. 330, 810-817
   Abstract »    Full Text »    PDF »
The chemokine Bv8/prokineticin 2 is up-regulated in inflammatory granulocytes and modulates inflammatory pain.
E. Giannini, R. Lattanzi, A. Nicotra, A. F. Campese, P. Grazioli, I. Screpanti, G. Balboni, S. Salvadori, P. Sacerdote, and L. Negri (2009)
PNAS 106, 14646-14651
   Abstract »    Full Text »    PDF »
Visualization of Chemokine Receptor Activation in Transgenic Mice Reveals Peripheral Activation of CCR2 Receptors in States of Neuropathic Pain.
H. Jung, S. Bhangoo, G. Banisadr, C. Freitag, D. Ren, F. A. White, and R. J. Miller (2009)
J. Neurosci. 29, 8051-8062
   Abstract »    Full Text »    PDF »
Transient Receptor Potential Vanilloid Gene Deletion Exacerbates Inflammation and Atypical Cardiac Remodeling After Myocardial Infarction.
W. Huang, J. Rubinstein, A. R. Prieto, L. V. Thang, and D. H. Wang (2009)
Hypertension 53, 243-250
   Abstract »    Full Text »    PDF »
Chemokine Action in the Nervous System.
R. J. Miller, W. Rostene, E. Apartis, G. Banisadr, K. Biber, E. D. Milligan, F. A. White, and J. Zhang (2008)
J. Neurosci. 28, 11792-11795
   Full Text »    PDF »
Properties of the Inner Pore Region of TRPV1 Channels Revealed by Block with Quaternary Ammoniums.
A. Jara-Oseguera, I. Llorente, T. Rosenbaum, and L. D. Islas (2008)
J. Gen. Physiol. 132, 547-562
   Abstract »    Full Text »    PDF »
Reactive Oxygen Species Derived from NOX1/NADPH Oxidase Enhance Inflammatory Pain.
M. Ibi, K. Matsuno, D. Shiba, M. Katsuyama, K. Iwata, T. Kakehi, T. Nakagawa, K. Sango, Y. Shirai, T. Yokoyama, et al. (2008)
J. Neurosci. 28, 9486-9494
   Abstract »    Full Text »    PDF »
Protein kinase C inhibits caveolae-mediated endocytosis of TRPV5.
S.-K. Cha, T. Wu, and C.-L. Huang (2008)
Am J Physiol Renal Physiol 294, F1212-F1221
   Abstract »    Full Text »    PDF »
Chemokines and the pathophysiology of neuropathic pain.
F. A. White, H. Jung, and R. J. Miller (2007)
PNAS 104, 20151-20158
   Abstract »    Full Text »    PDF »
Neurokinin-1 Receptor Enhances TRPV1 Activity in Primary Sensory Neurons via PKC{varepsilon}: A Novel Pathway for Heat Hyperalgesia.
H. Zhang, C.-L. Cang, Y. Kawasaki, L.-L. Liang, Y.-Q. Zhang, R.-R. Ji, and Z.-Q. Zhao (2007)
J. Neurosci. 27, 12067-12077
   Abstract »    Full Text »    PDF »
Increased visceral sensitivity to capsaicin after DSS-induced colitis in mice: spinal cord c-Fos expression and behavior.
N. Eijkelkamp, A. Kavelaars, S. Elsenbruch, M. Schedlowski, G. Holtmann, and C. J. Heijnen (2007)
Am J Physiol Gastrointest Liver Physiol 293, G749-G757
   Abstract »    Full Text »    PDF »
Dual Regulation of TRPV1 by Phosphoinositides.
V. Lukacs, B. Thyagarajan, P. Varnai, A. Balla, T. Balla, and T. Rohacs (2007)
J. Neurosci. 27, 7070-7080
   Abstract »    Full Text »    PDF »
Changes in Osmolality Sensitize the Response to Capsaicin in Trigeminal Sensory Neurons.
L. Liu, L. Chen, W. Liedtke, and S. A. Simon (2007)
J Neurophysiol 97, 2001-2015
   Abstract »    Full Text »    PDF »
Transient Receptor Potential Cation Channels in Disease.
B. Nilius, G. Owsianik, T. Voets, and J. A. Peters (2007)
Physiol Rev 87, 165-217
   Abstract »    Full Text »    PDF »
cDNA microarray analysis reveals fundamental differences in the expression profiles of primary human monocytes, monocyte-derived macrophages, and alveolar macrophages.
J. Li, D. K. Pritchard, X. Wang, D. R. Park, R. E. Bumgarner, S. M. Schwartz, and W. C. Liles (2007)
J. Leukoc. Biol. 81, 328-335
   Abstract »    Full Text »    PDF »
Impaired nociception and inflammatory pain sensation in mice lacking the prokineticin receptor PKR1: focus on interaction between PKR1 and the capsaicin receptor TRPV1 in pain behavior..
L. Negri, R. Lattanzi, E. Giannini, M. Colucci, F. Margheriti, P. Melchiorri, V. Vellani, H. Tian, M. De Felice, and F. Porreca (2006)
J. Neurosci. 26, 6716-6727
   Abstract »    Full Text »    PDF »
Selective local PMN recruitment by CXCL1 or CXCL2/3 injection does not cause inflammatory pain.
H. L. Rittner, S. A. Mousa, D. Labuz, K. Beschmann, M. Schafer, C. Stein, and A. Brack (2006)
J. Leukoc. Biol. 79, 1022-1032
   Abstract »    Full Text »    PDF »
Crosstalk between chemokines and neuronal receptors bridges immune and nervous systems.
N. Zhang and J. J. Oppenheim (2005)
J. Leukoc. Biol. 78, 1210-1214
   Abstract »    Full Text »    PDF »
Leukocytes in the regulation of pain and analgesia.
H. L. Rittner, H. Machelska, and C. Stein (2005)
J. Leukoc. Biol. 78, 1215-1222
   Abstract »    Full Text »    PDF »
Excitatory monocyte chemoattractant protein-1 signaling is up-regulated in sensory neurons after chronic compression of the dorsal root ganglion.
F. A. White, J. Sun, S. M. Waters, C. Ma, D. Ren, M. Ripsch, J. Steflik, D. N. Cortright, R. H. LaMotte, and R. J. Miller (2005)
PNAS 102, 14092-14097
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882