title: Topical azithromycin and clarithromycin inhibit acute and chronic skin inflammation in sensitized mice, with apparent selectivity for Th2-mediated processes in delayed-type hypersensitivity.
abstract: Macrolide antibiotics inhibit the secretion of Th1 cytokines while their effects on the release of Th2 cytokines are variable. We investigated molecular and cellular markers of Th1- and Th2-mediated inflammatory mechanisms and the anti-inflammatory activity of azithromycin and clarithromycin in phorbol 12-myristate 13-acetate (PMA) and oxazolone (OXA)-induced skin inflammation. Dexamethasone (50 μg/ear), azithromycin, and clarithromycin (500 μg/ear) reduced TNF-α and interleukin (IL)-1β concentration in ear tissue by inhibiting inflammatory cell accumulation in PMA-induced inflammation. In OXA-induced early delayed-type hypersensitivity (DTH), the macrolides (2 mg/ear) and dexamethasone (25 μg/ear) reduced ear tissue inflammatory cell infiltration and secretion of IL-4 while clarithromycin also decreased IFN-γ concentration. Macrolides showed better activity when administered after the challenge. In OXA-induced chronic DTH, azithromycin (1 mg/ear) reduced the number of ear tissue mast cells and decreased the concentration of IL-4 in ear tissue and of immunoglobulin (Ig)E in serum. Clarithromycin (1 mg/ear) reduced serum IgE concentration, possibly by a mechanism independent of IL-4, while both macrolides attenuated mast cell degranulation. In conclusion, azithromycin and clarithromycin attenuate pro-inflammatory cytokine production and leukocyte infiltration during innate immune reactions, while selectively affecting Th2 rather than Th1 immunity in DTH reactions.
authors.affiliation: Galapagos istraživački centar d.o.o., Prilaz baruna Filipovia 29, 10000, Zagreb, Croatia. Vanesa.IveticTkalcevic@glpg.com
authors.forename: Vanesa
authors.initials: V
authors.lastname: Ivetić Tkalčević
authors.forename: Snježana
authors.initials: S
authors.lastname: Cužić
authors.forename: Miroslava Dominis
authors.initials: MD
authors.lastname: Kramarić
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parnham
authors.forename: Vesna
authors.initials: V
authors.lastname: Eraković Haber
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use; D017963:Azithromycin / Q000008:administration & dosage* / Q000627:therapeutic use; D015550:Cell Degranulation / Q000187:drug effects; D017291:Clarithromycin / Q000008:administration & dosage* / Q000627:therapeutic use; D003877:Dermatitis, Contact / Q000188:drug therapy* / Q000276:immunology; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use; D004423:Ear; D006968:Hypersensitivity, Delayed / Q000188:drug therapy* / Q000276:immunology; D007073:Immunoglobulin E / Q000097:blood; D007371:Interferon-gamma / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D015847:Interleukin-4 / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology; D051379:Mice; D010081:Oxazolone; D012867:Skin / Q000276:immunology / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000893:Anti-Inflammatory Agents; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D010081:Oxazolone; D015847:Interleukin-4; D007073:Immunoglobulin E; D003907:Dexamethasone; D007371:Interferon-gamma; D017963:Azithromycin; D017291:Clarithromycin; D013755:Tetradecanoylphorbol Acetate