title: Interleukin-6 primarily produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response.
abstract: Interleukin-6 (IL-6) is critical for the lipopolysaccharide (LPS)-induced febrile response. However, the exact source(s) of IL-6 involved in regulating the LPS-elicited fever is still to be identified. One known source of IL-6 is hematopoietic cells, such as monocytes. To clarify the contribution of hematopoietically derived IL-6 to fever, we created chimeric mice expressing IL-6 selectively either in cells of hematopoietic or, conversely, in cells of non-hematopoietic origin. This was performed by extinguishing hematopoietic cells in wild-type (WT) or IL-6 knockout (IL-6 KO) mice by whole-body irradiation and transplanting them with new stem cells. Mice on a WT background but lacking IL-6 in hematopoietic cells displayed normal fever to LPS and were found to have similar levels of IL-6 protein in the cerebrospinal fluid (CSF) and in plasma and of IL-6 mRNA in the brain as WT mice. In contrast, mice on an IL-6 KO background, but with intact IL-6 production in cells of hematopoietic origin, only showed a minor elevation of the body temperature after peripheral LPS injection. While they displayed significantly elevated levels of IL-6 both in plasma and CSF compared with control mice, the increase was modest compared with that seen in LPS injected mice on a WT background, the latter being approximately 20 times larger in magnitude. These results suggest that IL-6 of non-hematopoietic origin is the main source of IL-6 in LPS-induced fever, and that IL-6 produced by hematopoietic cells only plays a minor role.
authors.affiliation: Linköping University, Faculty of Health Sciences, Department of Clinical and Experimental Medicine, Division of Cell Biology, SE-581 85 Linköping, Sweden.
authors.forename: Namik
authors.initials: N
authors.lastname: Hamzic
authors.forename: Yanjuan
authors.initials: Y
authors.lastname: Tang
authors.forename: Anna
authors.initials: A
authors.lastname: Eskilsson
authors.forename: Unn
authors.initials: U
authors.lastname: Kugelberg
authors.forename: Johan
authors.initials: J
authors.lastname: Ruud
authors.forename: Jan-Ingvar
authors.initials: JI
authors.lastname: Jönsson
authors.forename: Anders
authors.initials: A
authors.lastname: Blomqvist
authors.forename: Camilla
authors.initials: C
authors.lastname: Nilsberth
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D016026:Bone Marrow Transplantation / Q000379:methods; D005260:Female; D005334:Fever / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005720:Gamma Rays; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000172:deficiency / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011828:Radiation Chimera; D011897:Random Allocation
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D049452:Green Fluorescent Proteins
keywords: Bone marrow transplantation; Fever; Hematopoietic cells; Interleukin-6