A key role for gp130 expressed on peripheral sensory nerves in pathological pain.
Interleukin-6 (IL-6) is a key mediator of inflammation. Inhibitors of IL-6 or of its signal transducing receptor gp130 constitute a novel class of anti-inflammatory drugs, which raise great hopes for improved treatments of painful inflammatory diseases such as rheumatoid arthritis. IL-6 and gp130 may enhance pain not only indirectly through their proinflammatory actions but also through a direct action on nociceptors (i.e., on neurons activated by painful stimuli). We found indeed that the IL-6/gp130 ligand-receptor complex induced heat hypersensitivity both in vitro and in vivo. This process was mediated by activation of PKC-delta via Gab1/2/PI(3)K and subsequent regulation of TRPV1, a member of the transient receptor potential (TRP) family of ion channels. To assess the relevance of this direct pain promoting effect of IL-6, we generated conditional knock-out mice, which lack gp130 specifically in nociceptors, and tested them in models of inflammatory and tumor-induced pain. These mice showed significantly reduced levels of inflammatory and tumor-induced pain but no changes in immune reactions or tumor growth. Our results uncover the significance of gp130 expressed in peripheral pain sensing neurons in the pathophysiology of major clinical pain disorders and suggest their use as novel pain relieving agents in inflammatory and tumor pain.
Department of Physiology and Medical Physics, Division of Physiology, Innsbruck Medical University, Innsbruck, Austria.
Manfred
M
Andratsch
Norbert
N
Mair
Cristina E
CE
Constantin
Nadja
N
Scherbakov
Camilla
C
Benetti
Serena
S
Quarta
Christian
C
Vogl
Claudia A
CA
Sailer
Nurcan
N
Uceyler
Johannes
J
Brockhaus
Rudolf
R
Martini
Claudia
C
Sommer
Hanns Ulrich
HU
Zeilhofer
Werner
W
Müller
Rohini
R
Kuner
John B
JB
Davis
Stefan
S
Rose-John
Michaela
M
Kress
D000818:Animals; D002277:Carcinoma / Q000150:complications / Q000378:metabolism; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D006358:Hot Temperature; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000378:metabolism; D008175:Lung Neoplasms / Q000150:complications / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009619:Nociceptors / Q000378:metabolism; D010146:Pain / Q000209:etiology / Q000378:metabolism*; D017288:Pain Threshold; D010525:Peripheral Nerves / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D011984:Sensory Receptor Cells / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism
C494200:Il6st protein, mouse; D015850:Interleukin-6; D050822:Cytokine Receptor gp130