title: Development of non-antibiotic macrolide that corrects inflammation-driven immune dysfunction in models of inflammatory bowel diseases and arthritis.
abstract: Inflammation-driven immune dysfunction supports the development of several chronic human disorders including inflammatory bowel diseases and rheumatoid arthritis. Macrolides are effective antibiotics endowed with immunomodulatory effects. In this study we report the chemical synthesis and the pharmacological characterization of CSY0073, a non-antibiotic derivative of azithromycin. CSY0073 was tested for efficacy in two experimental models of colitis induced by administering mice with dextran sulfate (DSS) and trinitrobenzene sulphonic acid (TNBS) and in collagen induced arthritis. Like azithromycin, CSY0073 improved clinical, macroscopic and histopathological scores in mice administered DSS (12.5μmol/kg/day p.o.) and TNBS (45μmol/kg/day p.o.). When administered to TNBS-treated mice, CSY0073 effectively attenuated influx of neutrophils and macrophages into the colonic mucosa and reduced the intestinal expression pro-inflammatory cytokines TNFα, IL-2 and IFNγ. CSY0073 (0.1 to 10μM) counter-regulated TNFα, IFNγ, IL-12 and IL-23 release caused by exposure of mouse spleen monocytes and CD11b+ cells isolated from the colonic lamina propria to endotoxin. CSY0073 (25μmol/kg/day) reduced clinical scores in the collagen induced murine model of rheumatoid arthritis. In myeloid cells, CSY0073 (10μM) prevented the nuclear translocation of the p65 subunit of NF-κB and its binding to canonical NF-κB responsive elements. In summary, we report a novel class of non-antibiotic 14-member macrocycles with anti-inflammatory and immune-modulatory effects. CSY0073, the prototype of this new class of macrolides exerts counter-regulatory activity on NF-κB signaling. This study suggests the exploitation of non-antibiotic macrolides in the treatment of inflammatory disorders characterized by immune dysfunction.
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, University of Perugia, Italy. andrea.mencarelli@unipg.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Mencarelli
authors.forename: Eleonora
authors.initials: E
authors.lastname: Distrutti
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cipriani
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Palladino
authors.forename: Catherine
authors.initials: C
authors.lastname: Booth
authors.forename: Gregory
authors.initials: G
authors.lastname: Tudor
authors.forename: Jan-Hinrich
authors.initials: JH
authors.lastname: Guse
authors.forename: Ulrike
authors.initials: U
authors.lastname: Hahn
authors.forename: Micheal
authors.initials: M
authors.lastname: Burnet
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D017963:Azithromycin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D039481:CD11b Antigen / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D003094:Collagen / Q000494:pharmacology; D016264:Dextran Sulfate / Q000494:pharmacology; D004195:Disease Models, Animal; D055808:Drug Discovery; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000276:immunology; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D009092:Mucous Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D039481:CD11b Antigen; C568293:CSY 0073; D007155:Immunologic Factors; D016328:NF-kappa B; D017963:Azithromycin; D014302:Trinitrobenzenesulfonic Acid; D003094:Collagen; D016264:Dextran Sulfate