title: The IL-6-soluble IL-6Ralpha autocrine loop of endothelial activation as an intermediate between acute and chronic inflammation: an experimental model involving thrombin.
abstract: Thrombin is a procoagulant and proinflammatory molecule in vivo. In vitro, thrombin has been shown to induce endothelial activation, notably IL-8 secretion and adhesion molecule expression. In this study, we showed that thrombin may induce a new cascade leading from acute to chronic inflammation. Thrombin was able to induce the production of both IL-6 and monocyte chemotactic protein-1 (MCP-1) by HUVEC independently of IL-1alphabeta and TNF-alpha. Addition of physiological concentrations of exogenous soluble IL-6Ralpha (sIL-6Ralpha) to thrombin-activated HUVEC was sufficient to increase the amounts of MCP-1 produced, but not those of IL-8. These effects could be blocked by anti-IL-6 or anti-sIL-6Ralpha blocking mAb, demonstrating the existence of an autocrine loop of MCP-1 secretion, involving the IL-6/IL-6Ralpha/gp130 complex on HUVEC. In addition, we identified IL-8-activated neutrophils as a potential source of sIL-6Ralpha because IL-8 induced IL-6Ralpha shedding from the neutrophil membranes and increased in parallel sIL-6Ralpha concentrations in neutrophil supernatants. Furthermore, addition of neutrophils to thrombin-activated HUVEC significantly increased MCP-1 secretion, which could be decreased by blocking IL-6. Thus, thrombin-activated endothelium may induce a cascade of events characterized by IL-8 secretion, neutrophil local infiltration, and the release of IL-6Ralpha from neutrophil membranes. sIL-6Ralpha may then complex with IL-6 and increase the amount of MCP-1 produced by thrombin-activated endothelium, favoring monocyte infiltration, and the transformation of acute into chronic inflammation.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité 387, Hôpital Sainte-Marguerite, and Immunotech, a Beckman Coulter Company, Marseille, France.
authors.forename: V
authors.initials: V
authors.lastname: Marin
authors.forename: F A
authors.initials: FA
authors.lastname: Montero-Julian
authors.forename: S
authors.initials: S
authors.lastname: Grès
authors.forename: V
authors.initials: V
authors.lastname: Boulay
authors.forename: P
authors.initials: P
authors.lastname: Bongrand
authors.forename: C
authors.initials: C
authors.lastname: Farnarier
authors.forename: G
authors.initials: G
authors.lastname: Kaplanski
mesh_terms: D000208:Acute Disease; D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D001777:Blood Coagulation / Q000502:physiology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism*; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D002908:Chronic Disease; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism / Q000494:pharmacology; D046911:Macromolecular Substances; D051379:Mice; D023421:Models, Animal; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility; D013917:Thrombin / Q000494:pharmacology* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins
chemical_list: C475829:CXCL1 protein, human; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D046911:Macromolecular Substances; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D013917:Thrombin