Central role of IL-6 receptor signal-transducing chain gp130 in activation of L-selectin adhesion by fever-range thermal stress.
The physiological benefit of the febrile response is poorly understood. Here we show that fever-range thermal stress enhances the function of the L-selectin lymphocyte homing receptor through an interleukin-6 (IL-6)-dependent signaling mechanism. Thermal stimulation of L-selectin adhesion in vitro and in vivo is mediated by engagement of the gp130 signal-transducing chain by IL-6 and a soluble form of the IL-6 receptor-alpha (sIL-6Ralpha) binding subunit. Thermal control of adhesion is maintained in IL-6-deficient mice through a gp130-dependent compensatory mechanism mediated by IL-6-related cytokines (i.e., oncostatin M [OSM], leukemia inhibitory factor [LIF], and IL-11). Combined biochemical and pharmacological inhibitor (PD98059, U0126, SB203580, SP600125) approaches positioned MEK1/ERK1-2, but not p38 MAPK or JNK, in the IL-6/sIL-6Ralpha signaling pathway upstream of activation of L-selectin/cytoskeletal interactions and L-selectin avidity/affinity. These results highlight a role for gp130-linked IL-6/sIL-6Ralpha transsignaling in amplifying lymphocyte trafficking during febrile inflammatory responses.
Chen
Qing
Q
Department of Immunology, Roswell Park Cancer Institute, Carlton and Elm Streets, Buffalo, NY 14263, USA.
Wang
Wan Chao
WC
Bruce
Robert
R
Li
Hong
H
Schleider
David M
DM
Mulbury
Michael J
MJ
Bain
Mark D
MD
Wallace
Paul K
PK
Baumann
Heinz
H
Evans
Sharon S
SS
D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D050822:Cytokine Receptor gp130; D006358:Hot Temperature; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000502:physiology; D019041:L-Selectin / Q000502:physiology*; D008214:Lymphocytes / Q000502:physiology*; D048369:MAP Kinase Kinase 1; D008562:Membrane Glycoproteins / Q000276:immunology / Q000502:physiology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D019947:Receptors, Interleukin-6 / Q000276:immunology / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D015703:Antigens, CD; C494199:IL6ST protein, human; C494200:Il6st protein, mouse; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D019947:Receptors, Interleukin-6; D019041:L-Selectin; D050822:Cytokine Receptor gp130; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases