Suppressive efficacies of antimicrobial agents against human peripheral-blood mononuclear cells stimulated with T cell mitogen and bacterial superantigen

Abstract

The immunomodulatory efficacies of 12 antimicrobial agents clinically used were examined against T cell mitogen- or bacterial superantigen-induced proliferation of peripheral-blood mononuclear cells of healthy subjects. Minocycline (CAS 13614-98-7), rifampicin (CAS 13292-46-1), trimethoprim (CAS 738-70-5), and ribavirin (CAS 36791-04-5) significantly inhibited the proliferation of mitogen-stimulated mononuclear cells at 1 – 100 µg/ml (p < 0.001), whereas ofloxacin (CAS 82419-36-1) enhanced the proliferation (p < 0.001). Ampicillin (CAS 69-53-4), lincomycin (CAS 859-18-7), vancomycin (CAS 1404-93-9), sulfamethoxazole (CAS 723-46-6), fosfomycin (CAS 26016-99-9), Colistin (CAS 1264-72-8), and polymyxin B (CAS 1405-20-5) showed no significant effect. Minocycline, rifampicin, trimethoprim, and ribavirin also inhibited the proliferation of superantigen-stimulated peripheral-blood mononuclear cells at 1–100 µg/ml (< 0.001), whereas ofloxacin stimulated the proliferation (p < 0.001). Rifampicin and minocycline at 10–100 µg/ml significantly inhibited interleukin-2 production from mitogen-or superantigen-stimulated peripheral-blood mononuclear cells (p < 0.025). These results suggest that certain kinds of antimicrobial agents inhibited the proliferation of mitogen- and superantigen-stimulated human peripheral-blood mononuclear cells and suppressed interleukin-2 production from these cells. The ofloxacin effect is immunostimulative, while the drug did not influence the interleukin-2 production.

Key words

Antimicrobial agents, immunomodulatory effect - Human peripheral lymphocytes - Interleukin-2 - Toxic shock syndrome toxin 1

• References

• 1 Taylor JE, Ross DA, Goodacre JA. Group A streptococcal antigens and superantigens in the pathogenesis of autoimmune arthritis. Eur J Clin Invest. 1994; 24: 511-21
• 2 Hauk PJ, Hamid QA, Chrousos G.P, Leung DM. Induction of corticosteroid insensitivity in human PBMCs by microbial superantigens. J Allergy Clin Immunol. 2000; 105: 782-7
• 3 Rasmussen JE. The relationship between infection with group A beta hemolytic streptococci and the development of psoriasis. Pediatr Infect Dis J. 2000; 19: 153-4
• 4 Leung DY, Travers JB, Giorno R. Evidence for a streptococcal superantigen-driven process in acute guttate psoriasis. J Clin Invest. 1995; 96: 2106-12
• 5 Barker JN, Karabin G.D, Stoof TJ, Sarma VJ, Dixit VM, Nickoloff BJ. Detection of interferon-gamma mRNA in psoriatic epidermis by polymerase chain reaction. J Dermatol Sci. 1991; 2: 106-11
• 6 Schlaak JF, Buslau M, Jochum W, Hermann E, Girndt M, Gallati H et al T cells involved in psoriasis vulgaris belong to the Th1 subset. J Invest Dermatol. 1994; 102: 145-9
• 7 Bata-Csorgo Z, Hammerberg C, Voorhees JJ, Cooper KD. Kinetics and regulation of human keratinocyte stem cell growth in short-term primary ex vivo culture. Cooperative growth factors from psoriatic lesional T lymphocytes stimulate proliferation among psoriatic uninvolved, but not normal, stem keratinocytes. J Clin Invest. 1995; 95: 317-27
• 8 Szabo SK, Hammerberg C, Yoshida Y, Bata-Csorgo Z, Cooper KD. Identification and quantitation of interferon-gamma producing T cells in psoriatic lesions: localization to both CD4⁺ and CD8⁺ subsets. J Invest Dermatol. 1998; 111: 1072-8
• 9 Austin LM, Ozawa M, Kikuchi T, Walters IB, Krueger JG. The majority of epidermal T cells in psoriasis vulgaris lesions can produce type 1 cytokines, interferon-γ, interleu-kin-2, and tumor necrosis factor-α, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J Invest Dermatol. 1999; 13: 752-9
• 10 Hirano T, Oka K, Umezawa Y, Hirata M, Ohi T, Koga M. Individual pharmacodynamics assessed by antilymphocyte action predicts clinical cyclosporine-efficacy in psoriasis. Clin Pharmacol Ther. 1998; 63: 465-70
• 11 Haczku A, Alexander A, Brown P, Assoufi B, Li B, Kay AB et al The effect of dexamethasone, cyclosporine, and rapamycin on T-lymphocyte proliferation in vitro: comparison of cells from patients with glucocorticoid-sensitive and glucocorticoid-resistant chronic asthma. J Allergy Clin Immunol. 1994; 93: 510-9
• 12 Hirano T, Oka K, Takeuchi H, Sakurai E, Matsuno N, Nagao T et al Clinical significance of glucocorticoid pharmacodynamics assessed by anti-lymphocyte action in kidney transplantation: Marked difference between prednisolone and methylprednisolone. Transplantation. 1994; 57: 1341-8
• 13 Hirano T, Oka K, Takeuchi H, Kozaki K, Matsuno N, Nagao T et al Immunosuppressant pharmacodynamics on lymphocytes from healthy subjects and patients with chronic renal failure, nephrosis and psoriasis: possible implications for individual therapeutic efficacy. Clin Pharmacol Ther. 1997; 62: 652-64
• 14 Hirano T, Akashi T, Keira T, Oka K, Ihoya N, Yoshida M. Clinical impact of cyclosporine cellular-pharmacodynamics in minimal change nephrotic syndrome. Clin Pharmacol Ther. 2000; 68: 532-40
• 15 Kirkham BW, Corkill MM, Davison SC, Panayi G. S. Response to glucocorticoid treatment in rheumatoid arthritis: in vitro cell mediated immune assay predicts in vivo responses. J Rheumatol. 1991; 18: 821-5
• 16 Hirano T, Akashi T, Kido T, Oka K, Shiratori T, Miyaoka M. Immunosuppressant pharmacodynamics on peripheral-blood mononuclear cells from patients with ulcerative colitis. Int Immunopharmacol. 2002; 2: 1055-63
• 17 Fakhri S, Tulic M, Christodoulopoulos P, Fukakusa M, Frenkiel S, Leung DY et al Microbial superantigens induce glucocorticoid receptor beta and steroid resistance in a nasal explant model. Laryngoscope. 2004; 114: 887-92
• 18 Culic O, Erakovic V, Parnham MJ. Anti-inflammatory effects of macrolide antibiotics. Eur J Pharmacol. 2001; 429: 209-29
• 19 Komine M, Tamaki K. An open trial of oral macrolide treatment for psoriasis vulgaris. J Dermatol. 2000; 27: 508-12
• 20 Ohshima A, Takigawa M, Tokura Y. CD8+ cell changes in psoriasis associated with roxithromycin-induced clinical improvement. Eur J Dermatol. 2002; 11: 410-5
• 21 Tamaoki J, Kadota J, Takizawa H. Clinical implications of the immunomodulatory effects of macrolides. Am J Med. 2004; 117: 5S-11S
• 22 Tsai WC, Standiford TJ. Immunomodulatory effects of macrolides in the lung: lessons from in-vitro and in-vivo models. Curr Pharm Des. 2004; 10: 3081-93
• 23 Norris D. Mechanisms of action of topical therapies and the rationale for combination therapy. J Am Acad Dermatol. 2005; 53: 17-25
• 24 Hirano T, Oka K, Tamaki T. Gramicidin as a potent immunosuppressant for organ transplantation: Suppression of human lymphocyte blastogenesis in vitro and prolongation of heart allograft survival in the rat. J Pharmacol Exp Ther. 1995; 273: 223-9
• 25 Taira S, Katsuyama K, Konno O, Ashizawa T, Matsuno N, Nagao T et al Influence of bacterial superantigen TSST-1 against the anti-proliferative efficacy of immunosuppressive drugs and interleukin 2 production in peripheral blood mononuclear cells of hemodialysis patients and healthy subjects. Immunopharmacol Immunotoxicol. 2008; 30: 1-14
• 26 Zehavi-Willner T, Shalit I. Enhancement of interleukin-2 production in human lymphocytes by two new quinolone derivatives. Lymphokine Res. 1989; 8: 35-46
• 27 Kaminski MM, Sauer SW, Klemke CD, Süss D, Okun JG, Krammer PH et al Mitochondrial reactive oxygen species control T cell activation by regulating IL-2 and IL-4 expression: mechanism of ciprofloxacin-mediated immunosuppression. J Immunol. 2010; 184: 4827-41
• 28 Gillbert DN, Moellering RC, Epiopoulos GM, Sande MA. editors. The Sanford guide to antimicrobial therapy. 35th edition. Sanford (FL, USA): 2005
• 29 Rigopoulou EI, Abbott WG, Williams R, Naoumov NV. Direct evidence for immunomodulatory properties of ribavirin on T-cell reactivity to hepatitis C virus. Antiviral Res. 2006; 75: 36-42
• 30 Fukushima H, Hirano T, Shibayama N, Miwa K, Ito T, Saito M et al The role of immune response to Staphylococcus aureus superantigens and disease severity to the sensitivity to tacrolimus in atopic dermatitis. Int Arch Allergy Immunol. 2006; 141: 281-9
• 31 Riesbeck K. Immunomodulation by fluoroquinolones and other antibacterial agents. Eur J Clin Invest. 2006; 36: 671-3
• 32 Hall IH, Schwab U, Ward ES, Ives T. In vitro anti-inflammatory effects and immunomodulation by gemifloxacin in stimulated human THP-1 monocytes. Pharmazie. 2004; 59: 713-9
• 33 Hall IH, Schwab U, Ward ES, Ives T. Effects of alatrofloxacin, the parental prodrug of trovafloxacin, on phagocytic, anti-inflammatory and immunomodulation events of human THP-1 monocytes. Biomed Pharmacother. 2003; 57: 359-65
• 34 Dalhoff A, Shalit I. Immunomodulatory effects of quinolones. Lancet Infect Dis. 2003; 3: 359-71
• 35 Bessler H, Gurary N, Aloni D, Vishne TH, Sirota L. Effect of cefotaxime on cytokine production in newborns and adults in vitro . Biomed Pharmacother. 2000; 54: 410-4
• 36 Ingham E, Turnbull L, Kearney JN. The effects of minocycline and tetracycline on the mitotic response of human peripheral blood lymphocytes. J Antimicrob Chemother. 1991; 27: 607-17
• 37 McKee EE, Ferguson M, Bentley AT, Marks TA. Inhibition of mammalian mitochondrial protein synthesis by oxazoli-dinones. Antimicrob Agents Chemother. 2006; 50: 2042-9
• 38 Van den Bogert C, Dontje BH, Kroon AM. Doxycycline in combination chemotherapy of a rat leukemia. Cancer Res. 1988; 48: 6686-90
• 39 van den Bogert C, Dontje BH, Holtrop M, Melis TE, Romijn JC, van Dongen JW et al Arrest of the proliferation of renal and prostate carcinomas of human origin by inhibition of mitochondrial protein synthesis. Cancer Res. 1986; 46: 3283-9
• 40 Calleja C, Pascussi JM, Mani JC, Maurel P, Vilarem MJ. The antibiotic rifampicin is a nonsteroidal ligand and activator of the human glucocorticoid receptor. Nature Med. 1998; 4: 92-6
• 41 Ziglam HM, Daniels I, Finch RG. Immunomodulating activity of rifampicin. J Chemother. 2004; 16: 357-61
• 42 Ghilchik MW, Morris AS, Reeves DS. Immunosuppressive powers of the antibacterial agent trimethoprim. Nature. 1970; 227: 393-4
• 43 Uchiyama T, Imanishi K, Araake M, Saito S, Yan XJ, Fujikawa H et al Activation of murine T cells by toxic shock syndrome toxin-1. The toxin-binding structures expressed on murine accessory cells are MHC class II molecules. J Immunol. 1989; 143: 3175-82
• 44 Li LB, Goleva E, Hall CF, Ou LS, Leung DY. Superantigen-induced corticosteroid resistance of human T cells occurs through activation of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK-ERK) pathway. J Allergy Clin Immunol. 2004; 114: 1059-69
• 45 Edmead CE, Patel YI, Wilson A, Boulougouris G, Hall ND, Ward SG et al Induction of activator protein (AP)-l and nuclear factor-kappaB by CD28 stimulation involves both phosphatidylinositol 3-kinase and acidic sphingomyelinase signals. J Immunol. 1996; 157: 3290-7
• 46 Koike T, Yamagishi H, Hatanaka Y, Fukushima A, Chang JW, Xia Y et al A novel ERK-dependent signaling process that regulates interleukin-2 expression in a late phase of T cell activation. J Biol Chem. 2003; 278: 15685-92
• 47 Feldstein A, Kleiner D, Kravetz D, Buck M. Severe hepatocellular injury with apoptosis induced by a hepatitis C polymerase inhibitor. J Clin Gastroenterol. 2009; 43: 374-81
• 48 Govindarajan R, Leung GP, Zhou M, Tse CM, Wang J, Unadkat JD. Facilitated mitochondrial import of antiviral and anticancer nucleoside drugs by human equilibrative nucleoside transporter-3. Am J Physiol Gastrointest Liver Physiol. 2009; 296: G910-22