title: Linomide abolishes leukocyte adhesion and extravascular recruitment induced by tumor necrosis factor alpha in vivo.
abstract: The immunomodulator Linomide (roquinimex) ameliorates the development of numerous inflammatory and immunological diseases, including sepsis, arthritis, and encephalomyelitis. However, the mechanism underlying this protective effect of Linomide remains unclear. In this study, we wanted to evaluate the effect of Linomide treatment on the different steps in the extravasation process of leukocytes stimulated by tumor necrosis factor alpha (TNF-alpha) in vivo. For this purpose, we used intravital microscopy in the mouse cremaster muscle microcirculation. We found that pretreatment with Linomide dose-dependently (3-300 mg/kg) reduced TNF-alpha-induced leukocyte adhesion and tissue recruitment. Notably, at 300 mg/kg response to TNF-alpha was nearly abolished, i.e. leukocyte adhesion was decreased by 83% and recruitment by 86%. In fact, the anti-inflammatory effect of this dose of Linomide corresponded in magnitude to the potency of 10 mg/kg of dexamethasone. Moreover, administration of Linomide did not alter the systemic leukocyte counts. On the other hand, 1-10 mg/kg of dexamethasone decreased the circulating number of mononuclear leukocytes by 77%. Taken together, our novel findings demonstrate that Linomide is a potent inhibitor of leukocyte adhesion and recruitment in cytokine-activated tissues. These data may help explain the documented protection provided by Linomide in inflammatory diseases characterized by cytokine and leukocyte accumulation.
authors.affiliation: Department of Surgery, Malmö University Hospital, Lund University, Sweden.
authors.forename: X W
authors.initials: XW
authors.lastname: Zhang
authors.forename: G
authors.initials: G
authors.lastname: Hedlund
authors.forename: P
authors.initials: P
authors.lastname: Borgström
authors.forename: K E
authors.initials: KE
authors.lastname: Arfors
authors.forename: H
authors.initials: H
authors.lastname: Thorlacius
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000494:pharmacology; D006912:Hydroxyquinolines / Q000494:pharmacology*; D007958:Leukocyte Count; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008833:Microcirculation / Q000187:drug effects; D018715:Microscopy, Video; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects; D019007:P-Selectin / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D000276:Adjuvants, Immunologic; D005938:Glucocorticoids; D006912:Hydroxyquinolines; D019007:P-Selectin; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C045282:roquinimex; D003907:Dexamethasone