title: RAGE is the major receptor for the proinflammatory activity of HMGB1 in rodent macrophages.
abstract: Abstract High-mobility group box chromosomal protein 1 (HMGB1) is a protein with both intranuclear functions and extracellular cytokine-like effects. In this report, we study possible candidate receptors for HMGB1 on macrophages (Mphi) and define pathways activated by HMGB1 binding. Bone marrow Mphi were prepared from Dark Agouti (DA) rats and stimulated in vitro with HMGB1. The kinetics of tumour necrosis factor (TNF) production, NO production, activation of p38 mitogen-activated protein kinase (MAPK), p44/42 MAPK- and SAPK/JNK-signalling pathways, nuclear translocation of nuclear factor kappa B (NF-kappaB) and HMGB1-induced upregulation of major histocompatibility complex (MHC) class II and CD86 were analysed. Mphi from interleukin (IL)-1 receptor type I-/-, Toll-like receptor 2 (TLR2-/-) and RAGE-/- mice were used to investigate the role of these receptors in HMGB1 signalling. HMGB1 induced TNF and NO production by Mphi, phosphorylation of all investigated MAP kinase pathways and NF-kappaB translocation, and expression of MHC class II was increased. Mphi from RAGE-/- mice produced significantly lower amounts of TNF, IL-1beta and IL-6, while IL-1RI-/- and TLR2-/- Mphi produced cytokine levels comparable with wildtype controls in response to HMGB1 stimulation. We conclude that HMGB1 has the potential to induce a proinflammatory phenotype in Mphi, with RAGE as the major activation-inducing receptor.
authors.affiliation: Department of Medicine, Rheumatology Unit, Karolinska Institutet, Stockholm, Sweden.
authors.forename: R
authors.initials: R
authors.lastname: Kokkola
authors.forename: A
authors.initials: A
authors.lastname: Andersson
authors.forename: G
authors.initials: G
authors.lastname: Mullins
authors.forename: T
authors.initials: T
authors.lastname: Ostberg
authors.forename: C-J
authors.initials: CJ
authors.lastname: Treutiger
authors.forename: B
authors.initials: B
authors.lastname: Arnold
authors.forename: P
authors.initials: P
authors.lastname: Nawroth
authors.forename: U
authors.initials: U
authors.lastname: Andersson
authors.forename: R A
authors.initials: RA
authors.lastname: Harris
authors.forename: H E
authors.initials: HE
authors.lastname: Harris
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D024243:HMGB1 Protein / Q000378:metabolism; D006609:High Mobility Group Proteins / Q000378:metabolism / Q000494:pharmacology*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism* / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D010766:Phosphorylation; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D012097:Repressor Proteins / Q000378:metabolism / Q000494:pharmacology*; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D006609:High Mobility Group Proteins; D000949:Histocompatibility Antigens Class II; D018836:Inflammation Mediators; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D011994:Recombinant Proteins; D012097:Repressor Proteins; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D048049:Extracellular Signal-Regulated MAP Kinases