Research Article| Volume 38, ISSUE 1, P47-55, April 2005

Download started.


Nadifloxacin, an antiacne quinolone antimicrobial, inhibits the production of proinflammatory cytokines by human peripheral blood mononuclear cells and normal human keratinocytes



      Acne vulgaris is a chronic inflammatory disease involving colonization of Propionibacterium acnes (P. acnes), activation of neutrophils and lymphocytes. Circumstantial evidence suggests that antigen-independent and -dependent immune responses against P. acnes are involved in the pathogenesis of inflammatory acne. Epidermal keratinocytes are also suggested to be involved in initiation and progression of cutaneous inflammation. Nadifloxacin, a fluorinated quinolone, has potent antimicrobial activities against Gram-negative and -positive microbes and is used to treat multiple inflamed acne lesions. However, its effect on immune conferring cells such as mononuclear cells and keratinocytes has not been examined.


      To evaluate the possible involvement of potential anti-inflammatory activity of nadifloxacin in its therapeutic effect on inflammatory acne, we examined the effects of nadifloxacin, in comparison with other antibiotics used to treat acne vulgaris, on cytokine production by human peripheral blood mononuclear cells (PBMC) and keratinocytes.


      Cytokine production by PBMC was determined after treatment with heat-killed P. acnes in the presence or absence of antimicrobials using a real-time PCR and ELISA. Cultured human epidermal keratinocytes were stimulated by IFN-γ plus IL-1β and the effects of antimicrobials were examined by using ELISA.


      Nadifloxacin as well as macrolide antibiotics and clindamycin inhibited IL-12 and IFN-γ production by PBMC stimulated by heat-killed P. acnes. The drug also inhibited the IL-1α, Il-6, IL-8 and GM-CMS production by keratinocytes treated with IFN-γ plus IL-1β.


      Inhibitory effects of nadifloxacin to activate T cells and keratinocytes may be involved at least in part in the mechanism of its therapeutic effect against inflammatory acne.


      PBMC (peripheral blood mononuclear cell), NDFX (nadifloxacin), LVFX (levofloxacin)


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Dermatological Science
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Norris J.F.
        • Cunliffe W.J.
        A histological and immunohistological study of early acne lesions.
        Br J Dermatol. 1988; 118: 651-659
        • Jeremy A.H.T.
        • Holland D.B.
        • Roberts S.G.
        • Thomson K.F.
        • Cunliffe W.J.
        Inflammatory events are involved in acne lesion initiation.
        J Invest Dermatol. 2003; 121: 20-27
        • Vowels B.R.
        • Yang S.
        • Leyden J.J.
        Induction of proinflammatory cytokines by soluble factor of Propionibacterium acnes: implications for chronic inflammatory acne.
        Infect Immun. 1995; 63: 3158-3165
        • Kim J.
        • Ochoa M.T.
        • Krutzik S.R.
        • Takeuchi O.
        • Uematsu S.
        • Legaspi A.J.
        • et al.
        Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses.
        J Immunol. 2002; 169: 1535-1541
        • Kersey P.
        • Sussman M.
        • Dahl M.
        Delayed skin test reactivity to Propionibacterium acnes correlates with severity of inflammation in acne vulgaris.
        Br J Dermatol. 1980; 103: 651-655
        • Webster G.F.
        Inflammatory acne represents hypersensitivity to Propionibacterium acnes.
        Dermatology. 1998; 196: 80-81
        • Kreuter A.
        • Schlottmann R.
        • Altmeyer P.
        • Brockmeyer N.H.
        Acne vulgaris as an immune reconstitution syndrome in a patient with AIDS after initiation of antiretroviral therapy.
        J Eur Acad Dermatol Venereol. 2002; 16: 638
        • Holland D.B.
        • Jeremy A.H.
        • Roberts S.G.
        • Seukeran D.C.
        • Layton A.M.
        • Cunliffe W.J.
        Inflammation in acne scarring: a comparison of the responses in lesions from patients prone and not prone to scar.
        Br J Dermatol. 2004; 150: 72-81
        • Jeremy AHT
        • Holland D.B.
        • Roberts S.G.
        • Thomson K.F.
        • Cunliffe W.J.
        Inflammatory events are involved in acne lesion initiation.
        J Invest Dermatol. 2003; 121: 20-27
        • Layton A.M.
        • Morris C.
        • Cunliffe W.J.
        • Ingham E.
        Immunohistochemical investigation of evolving inflammation in lesions of acne vulgaris.
        Exp Dermatol. 1998; 7: 191-197
        • Koreck A.
        • Pivarcsi A.
        • Dobozy A.
        • Kemény L.
        The role of innate immunity in the pathogenesis of acne.
        Dermatology. 2003; 206: 96-105
        • Nozaki S.
        • Feliciani C.
        • Sauder D.N.
        Keratinocyte cytokines.
        Adv Dermatol. 1992; 7: 83-100
        • McKenzie R.C.
        • Sauder D.N.
        The role of keratinocyte cytokines in inflammation and immunity.
        J Invest Dermatol. 1990; 95: 105S-107S
        • Ansel J.
        • Perry P.
        • Brown J.
        • Damm D.
        • Phan T.
        • Hart C.
        • et al.
        Cytokine modulation of keratinocyte cytokines.
        J Invest Dermatol. 1990; 94: 101S-107S
        • Klunker S.
        • Trautmann A.
        • Akdis M.
        • Verhagen J.
        • Schmid-Grendelmeier P.
        • Blaser K.
        • et al.
        A second step of chemotaxis after transendothelial migration: keratinocytes undergoing apoptosis release IFN-gamma-inducible protein 10, monokine induced by IFN-gamma, and IFN-gamma-inducible alpha-chemoattractant for T cell chemotaxis toward epidermis in atopic dermatitis.
        J Immunol. 2003; 171: 1078-1084
        • Ishikawa H.
        • Tabusa F.
        • Miyamoto H.
        • Kano M.
        • Ueda H.
        • Tamaoka H.
        • et al.
        Studies on antibacterial agents. I. Synthesis of substituted 6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acids.
        Chem Pharm Bull. 1989; 37: 2103-2108
        • Akamatsu H.
        • Sasaki H.
        • Kurokawa I.
        • Nishijima S.
        • Asada Y.
        • Niwa Y.
        Effect of nadifloxacin on neutrophil functions.
        J Int Med Res. 1995; 23: 19-26
        • Pittelkow M.R.
        • Scott R.E.
        New techniques for the in vitro culture of human skin keratinocytes and perspectives on their use for grafting of patients with extensive burns.
        Mayo Clin Proc. 1986; 61: 771-777
        • Culic O.
        • Erakovic V.
        • Parnham M.
        Anti-inflammatory effects of macrolide antibiotics.
        Eur J Pharmacol. 2001; 429: 209-229
        • Ianaro A.
        • Ialenti A.
        • Maffia P.
        • Sautebin L.
        • Rombola L.
        • Carnuccio R.
        • et al.
        Anti-inflammatory activity of macrolide antibiotics.
        J Pharmacol Exp Ther. 2000; 292: 156-163
        • Morikawa K.
        • Zhang J.
        • Nonaka M.
        • Morikawa S.
        Modulatory effect of macrolide antibiotics on the Th1- and Th2-type cytokine production.
        Int J Antimicrob Agents. 2002; 19: 53-59
        • Matsuoka N.
        • Eguchi K.
        • Kawakami A.
        • Tsuboi M.
        • Kawabe Y.
        • Aoyagi T.
        • et al.
        Inhibitory effect of clarithromycin on costimulatory molecule expression and cytokine production by synovial fibroblast-like cells.
        Clin. Exp. Immunol. 1996; 104: 501-508
        • Morikawa K.
        • Watabe H.
        • Araake M.
        • Morikawa S.
        Modulatory effect of antibiotics on cytokine production by human monocytes in vitro.
        Antimicrob Agents Chemother. 1996; 40: 1366-1370
        • Schultz M.J.
        • Speelman P.
        • Zaat S.
        • van Deventer S.J.H.
        • van der Poll T.
        Erythromycin inhibits tumor necrosis factor alpha and interleukin 6 production induced by heat-killed Streptococcus pneumoniae in whole blood.
        Antimicrob Agents Chemother. 1998; 42: 1605-1609
        • Kawada A.
        • Aragane Y.
        • Tezuka T.
        Levofloxacin is effective for inflammatory acne and achieves high levels in the lesions: an open study.
        Dermatology. 2002; 204: 301-302
        • Akamatsu H.
        • Horio T.
        Concentration of roxithromycin in the lesion of acne vulgaris.
        J Int Med Res. 2001; 29: 537-540
        • Leyden J.
        New understandings of the pathogenesis of acne.
        J Am Acad Dermatol. 1995; 32: S15-S25
        • Trinchieri G.
        Interleukin-12 and the regulation of innate resistance and adaptive immunity.
        Nat Rev Immunol. 2003; 3: 133-146
        • Braga G.
        • Ananias Z.
        • Mussalem S.
        • Squaiella C.
        • Longhini L.
        • Mariano M.
        • et al.
        Treatment with Propionibacterium acnes modulates the late phase reaction of immediate hypersensitivity in mice.
        Immunol Lett. 2003; 88: 163-169
        • Riesbeck K.
        Immunomodulating activity of quinolones: review.
        J Chemother. 2002; 14: 3-12
        • Araujo F.G.
        • Slifer T.L.
        • Remington J.S.
        Effect of moxifloxacin on secretion of cytokines by human monocytes stimulated with lipopolysaccharide.
        Clin Microbiol Infect. 2002; 8: 26-30
        • Jain A.
        • Sangal L.
        • Basal E.
        • Kaushal G.P.
        • Agarwal S.K.
        Anti-inflammatory effects of erythromycin and tetracycline on Propionibacterium acnes induced production of chemotactic factors and reactive oxygen species by human neutrophils.
        Dermatol Online J. 2002; 8: 2
        • Graham G.M.
        • Farrar M.D.
        • Cruse-Sawyer J.E.
        • Holland K.T.
        • Ingham E.
        Proinflammatory cytokine production by human keratinocytes stimulated with Propionibacterium acnes and P. acnes GroEL.
        Br J Dermatol. 2004; 150: 421-428
        • Freedberg I.M.
        • Tomic-Canic M.
        • Komine M.
        • Blumenberg M.
        Keratins and the keratinocyte activation cycle.
        J Invest Dermatol. 2001; 116: 633-640
        • Pessina A.
        • Raimondi A.
        • Cerri A.
        • Piccirillo M.
        • Neri M.G.
        • Croera C.
        • et al.
        High sensitivity of human epidermal keratinocytes (HaCaT) to topoisomerase inhibitors.
        Cell Prolif. 2001; 34: 243-252
        • Kobayashi M.
        • Shimauchi T.
        • Hino R.
        • Tokura Y.
        Roxithromycin downmodulates Th2 chemokine production by keratinocytes and chemokine receptor expression on Th2 cells: its dual inhibitory effects on the ligands and the receptors.
        Cell Immunol. 2004; 228: 27-33
        • Wakita H.
        • Tokura Y.
        • Furukawa F.
        • Takigawa M.
        The macrolide antibiotic, roxithromycin suppresses IFN-γ-mediated immunological functions of cultured normal human keratinocytes.
        Biol Pharm Bull. 1996; 19: 224-227