The alarmin HMGB1 acts in synergy with endogenous and exogenous danger signals to promote inflammation
| Autor: | Helena Erlandsson Harris, Hulda Sigridur Hreggvidsdottir, Ann-Charlotte Aveberger, Lars Ottosson, Lena Klevenvall, Hanna Schierbeck, Ulf Andersson, Heidi Wähämaa, Karin Palmblad, Therese Östberg |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Lipopolysaccharides
Cell Survival Immunology Interleukin-1beta chemical and pharmacologic phenomena HMGB1 Ligands Proinflammatory cytokine Arthritis Rheumatoid Immunology and Allergy Animals Humans Biotinylation Nuclear protein HMGB1 Protein Cells Cultured Inflammation biology Interleukin-6 Synovial Membrane Cell Biology Fibroblasts Toll-Like Receptor 1 Coculture Techniques Recombinant Proteins Toll-Like Receptor 2 Rats Toll-Like Receptor 4 Biochemistry Oligodeoxyribonucleotides RANKL Toll-Like Receptor 9 biology.protein TLR4 Leukocytes Mononuclear Cytokines Tumor necrosis factor alpha Inflammation Mediators Cell activation Signal Transduction |
| Zdroj: | Journal of leukocyte biology. 86(3) |
| ISSN: | 1938-3673 |
| Popis: | A prototypic mechanism for enhancement of inflammation by an endogenous molecule is described. The nuclear protein HMGB1 has previously been demonstrated to act as an alarmin and to promote inflammation upon extracellular release, yet its mode of action is still not well defined. Access to highly purified HMGB1 preparations from prokaryotic and eukaryotic sources enabled studies of activation of human PBMC or synovial fibroblast cultures in response to HMGB1 alone or after binding to cofactors. HMGB1 on its own could not induce detectable IL-6 production. However, strong enhancing effects on induction of proinflammatory cytokine production occurred when the protein associated with each of the separate proinflammatory molecules, rhIL-1β, the TLR4 ligand LPS, the TLR9 ligand CpG-ODN, or the TLR1-TLR2 ligand Pam3CSK4. The bioactivities were recorded in cocultures with preformed HMGB1 complexes but not after sequential or simultaneous addition of HMGB1 and the individual ligands. Individual A-box and B-box domains of HMGB1 had the ability to bind LPS and enhance IL-6 production. Heat denaturation of HMGB1 eliminated this enhancement. Cocultures with HMGB1 and other proinflammatory molecules such as TNF, RANKL, or IL-18 did not induce enhancement. HMGB1 thus acts broadly with many but not all immunostimulatory molecules to amplify their activity in a synergistic manner. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text