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.

Fever is associated with increased survival during acute infection, although its mechanism of action is largely unknown. This study found evidence of an unexpectedly integrated mechanism by which fever-range temperatures stimulate lymphocyte homing to secondary lymphoid tissues by increasing L-selectin and ␣4␤7 integrin-dependent adhesive interactions between circulating lymphocytes and specialized high endothelial venules (HEV). Exposure of splenic lymphocytes in vivo to fever-like whole-body hyperthermia (WBH; 39.8 ؎ 0.2°C for 6 hours) stimulated both L-selectin and IntroductionSystemic fever and local increases in temperature at sites of inflammation are cardinal features of host responses to pathogenic stimuli. Although the highly conserved fever response is linked to increased survival, 1,2 the mechanisms underlying the protective action of fever have not been fully elucidated. A central locus of control of the host immune response to foreign pathogens resides at the leukocyte-endothelial interface. To fight infections in peripheral tissues, blood-borne lymphocytes gain entry across specialized high endothelial venules (HEV) in secondary lymphoid organs (ie, lymph nodes [LN] and Peyer patches [PP]) and at extralymphoid sites of infection. Lymphocyte adhesion to HEV is initiated by the L-selectin and ␣4␤7 integrin adhesion molecules on the microvillous processes of lymphocytes. 3,4 These molecules mediate the initial attachment and slow rolling of lymphocytes on HEV counterreceptors under hemodynamic shear conditions. Subsequent G-protein-dependent chemokine activation of a ␤2-integrin, lymphocyte function-associated antigen 1 (LFA-1), results in firm adhesion of lymphocytes to HEV and transendothelial migration. Lymphocyte-HEV interactions in LN are initiated exclusively by L-selectin recognition of sialomucin-like receptors termed peripheral lymph node addressins (PNAd), which are identified by the MECA-79 monoclonal antibody (mAb). [3][4][5][6] In PP, L-selectin and ␣4␤7 integrins initiate lymphocyte tethering on HEV through interactions with distinct domains of MECA-367 mAb-reactive mucosal addressin cell adhesion molecule-1 (MAdCAM-1). 3,7 Mammals respond to natural infection or inflammatory stimuli (eg, pyrogenic cytokines, bacterial lipopolysaccharide, and turpentine) with a mild to moderate fever (1-4°C above normal body temperature). 1,2,8 Fever-range temperatures are associated with enhancement of the innate and adaptive arms of the immune response through augmentation of T-cell proliferation and cytotoxicity, bioactivity of inflammatory cytokines (eg, interferon (IFN)-␣), and neutrophil motility and chemotaxis. 1,2 Recent studies suggest that the highly efficient adhesion mechanism for lymphocyte recirculation can also be amplified by fever-range hyperthermia. In this regard, direct exposure of human and murine lymphocytes to long-duration, fever-range temperatures in vitro markedly stimulates both L-selectin and ␣4␤7 integrin-dependent adhesion to HEV in frozen-section assays. [9][10][11][12] I...