title: Conservation of IL-6 trans-signaling mechanisms controlling L-selectin adhesion by fever-range thermal stress.
abstract: Fever is associated with improved survival during infection in endothermic and ectothermic species although the protective mechanisms are largely undefined. Previous studies indicate that fever-range thermal stress increases the binding activity of the L-selectin homing receptor in human or mouse leukocytes, thereby promoting trafficking to lymphoid tissues across high endothelial venules (HEV). Here, we examined the evolutionary conservation of thermal regulation of L-selectin-like adhesion. Leukocytes from animals representing four taxa of vertebrates (mammals, avians, amphibians, teleosts) were shown to mediate L-selectin-like adhesion under shear to MECA-79-reactive ligands on mouse HEV in cross-species in vitro adherence assays. L-selectin-like binding activity was markedly increased by fever-range thermal stress in leukocytes of all species examined. Comparable increases in L-selectin-like adhesion were induced by thermal stress, IL-6, or the IL-6/soluble IL-6 receptor fusion protein, hyper-IL-6. Analysis of the molecular basis of thermal regulation of L-selectin-like adhesion identified a common IL-6 trans-signaling mechanism in endotherms and ectotherms that resulted in activation of JAK/STAT signaling and was inhibited by IL-6 neutralizing antibodies or recombinant soluble gp130. Conservation of IL-6-dependent mechanisms controlling L-selectin adhesion over hundreds of millions of years of vertebrate evolution strongly suggests that this is a beneficial focal point regulating immune surveillance during febrile inflammatory responses.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263-0001, USA.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Appenheimer
authors.forename: Rachael A
authors.initials: RA
authors.lastname: Girard
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.forename: Wan-Chao
authors.initials: WC
authors.lastname: Wang
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Bankert
authors.forename: Joy
authors.initials: J
authors.lastname: Hardison
authors.forename: Mark D
authors.initials: MD
authors.lastname: Bain
authors.forename: Frank
authors.initials: F
authors.lastname: Ridgley
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Sarcione
authors.forename: Sandra
authors.initials: S
authors.lastname: Buitrago
authors.forename: Sonja
authors.initials: S
authors.lastname: Kothlow
authors.forename: Bernd
authors.initials: B
authors.lastname: Kaspers
authors.forename: Jacques
authors.initials: J
authors.lastname: Robert
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Heinz
authors.initials: H
authors.lastname: Baumann
authors.forename: Sharon S
authors.initials: SS
authors.lastname: Evans
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D002448:Cell Adhesion / Q000276:immunology; D002478:Cells, Cultured; D017124:Conserved Sequence; D004285:Dogs; D019143:Evolution, Molecular; D005334:Fever / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D019041:L-Selectin / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011485:Protein Binding / Q000276:immunology; D011817:Rabbits; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D013312:Stress, Physiological / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology