Macrolides and immunity: effects of erythromycin and spiramycin on human mononoclear cell proliferation

Roche, Yvon; Gougerot‐Pocidalo, Marie‐Anne; Fay, Michèle; Forest, Nadine; Pocidalo, J J

doi:10.1093/jac/17.2.195

Cited by 52 publications

(25 citation statements)

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“…Furthermore, their different pharmacokinetic properties, especially with respect to their biological half-lives and intracellular concentrations at a given time (9,16,27,28), could explain their differential effects on IL-6 production within the same group. Indeed, differences in their interactions with phagocytes have already been shown (24,32). This is the first time, to our knowledge, that an antibiotic has been shown to increase IL-6 production.…”

Section: Resultsmentioning

confidence: 62%

Differential modulation of cytokine production by macrolides: interleukin-6 production is increased by spiramycin and erythromycin

Bailly

Pocidalo

Fay

et al. 1991

Antimicrob Agents Chemother

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Antibiotics do not act alone but act in conjunction with the host defense system. In pairticular, it has been shown that some antibiotics can modify cytokine production. We compared the in vitro effiects of three macrolides (roxithroinycin, spiramycin, and erythromycin) actively concentrated by leukocytes on interleukinla, (IL-la), IL-1p, , and tumor necrosis factor alpha. production by human monocytes stimulated with lipopolysaccharide. Our results show that the three macrolides tested have different effects on production of these cytokines. Spiramycin and, to a lesser extent, erythromycin increased total IL-6 production without affecting IL-la, IL-1j0, or tumor necrosis factor alpha production, whereas roxithromycin had no effect. To our knowledge, this is the first time that an antibiotic has been shown to increase IL-6 production.Over the last 20 years, a growing interest in the study of interactions between antimicrobial agents and host defense systems has arisen. In effect, a wide range of antimicrobial agents administered in vivo or in vitro have been reported to modify host immune responses (14,17,31), including cytokine production (3,4,20,29,30).Interleukin-la (IL-la), and IL-1p, IL-6, and tumor necrosis factor alpha (TNF-a) are the major cytokines produced by mononuclear phagocytes (6, 10, 23, 34). They mediate a wide range of biological activities that play a critical role in the induction of inflammatory and immune responses. Although these cytokines are biochemically and immunologically distinct proteins transcribed from different genes, they share a number of activities, such as the induction of fever and acute-phase protein synthesis by the liver (5,12,15,26). They have also been found to exhibit synergy, and each can modulate the production of the others (1,25,33).Macrolides are a class of antibiotics taken up and concentrated by leukocytes; as a result, they can reach intracellular concentrations far higher than those attained in the extracellular medium (8,21,28 Cytokine production. Following adherence, the cells were washed, and 1 ml of fresh serum-free medium was added to the monolayers with 10 p,g of lipopolysaccharide (LPS) (Escherichia coli O.55:B5; Difco) per ml and with or without various concentrations of the antibiotics (1, 10, and 50 ,ug/ml). Cultures were incubated for 18 h at 37°C in a humidified atmosphere of 95% air and 5% CO2. To determine extracellular cytokine concentrations, cell-free supernatants were collected, centrifuged at 800 x g for 10 min, and stored at -70°C until assay. To determine cell-associated cytokine concentrations, the cells remaining in the wells were covered with 1 ml of fresh medium, lysed with 3-[(3-cholamidopropyl)-dimethyl-ammonio]-1-propanesulfonate (CHAPS) (9 mM; Sigma) for 30 min, and stored at -70°C until assay. Addition of CHAPS to any of the recombinant cytokines used in this experiment did not modify the immunoassays.

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Section: Resultsmentioning

confidence: 62%

Differential modulation of cytokine production by macrolides: interleukin-6 production is increased by spiramycin and erythromycin

Bailly

Pocidalo

Fay

et al. 1991

Antimicrob Agents Chemother

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“…The results of these studies demonstrate that EM suppressed human lymphocyte proliferation in vitro (22,33).…”

Section: Methodsmentioning

confidence: 70%

“…Although the mechanism of the efficacy is uncertain, several hypotheses have been proposed, such as the immunomodulatory action of macrolide antibiotics. Macrolide antibiotics modulate the functions of inflammatory cells such as polymorphonuclear leukocytes, lymphocytes and macrophages (1,33). In addition, macrolide antibiotics directly affect airway secretory cell (12) and epithelial cell (35) functions.…”

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confidence: 99%

Effect of Macrolide Antibiotics on Macrophage Functions

Fujita

Negayama

et al. 1996

Microbiology and Immunology

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Macrolide antibiotics have a variety of actions other than antimicrobial activities. Recently, it has been suggested that macrolide antibiotics act as immunomodulators.In this study, we evaluated the effects of macrolide antibiotics on macrophage functions.For the macrophage, we used the mouse macrophage cell line J774.1. The following effects of macrolide antibiotics on macrophage functions were evaluated: the effect of macrolide antibiotics on macrophage growth; the phagocytosis of beads; cytocidal activity against Candida albicans; and chemotaxis to lipopolysaccharide (LPS). Macrolide antibiotics except for azithromycin significantly stimulated the growth of the macrophage. In addition, pretreatment with macrolide antibiotics except for roxithromycin significantly stimulated the macrophage phagocytosis of beads, macrophage chemotaxis to LPS, and macrophage cytocidal activity against Candida albicans. These results suggest that macrolide antibiotics stimulate macrophage functions. There is increasing evidence that long-term administration of the macrolide antibiotic erythromycin (EM) is effective in the treatment of chronic respiratory infections, probably through actions other than its antimicrobial properties (19). Although the mechanism of the efficacy is uncertain, several hypotheses have been proposed, such as the immunomodulatory action of macrolide antibiotics. Macrolide antibiotics modulate the functions of inflammatory cells such as polymorphonuclear leukocytes, lymphocytes and macrophages (1, 33). In addition, macrolide antibiotics directly affect airway secretory cell (12) and epithelial cell (35) functions. These effects are proposed to explain the efficacy of macrolides in the treatment of inflammatory airway diseases. Several studies have been conducted concerning the interaction between phagocytic cells and macrolide antibiotics. However, there are few reports that evaluate the interaction between macrophage functions and several macrolide antibiotics. With this background, we evaluated various aspects of the interaction between four macrolide antibiotics and macrophages. These studies included the effect on growth, effect on phagocytic activity, effect on chemotaxis to lipopolysaccharide (LPS), and effect of cytotoxicity against Candida albicans. Materials and MethodsMacrophage. We used a murine macrophage cell line, J774.1. This cell line was obtained from the RIKEN Cell Bank (Ibaraki, Japan). This cell line was cultured in RPMI-1640 medium with 10% fetal bovine serum (FBS).Antibiotics. The EM (Japan Dynabot Co., Tokyo), clarithromycin (CAM, Japan Dynabot Co.), roxithromycin (RXM, Roussel Uclaf, Paris, France), and azithromycin (AZM, Pfizer Pharmaceuticals Inc., Japan) were provided by the respective manufacturers. These 4 drugs were dissolved in 90% methanol at a concentration of 2 mg/ml as a stock solution; then diluted with RPMI-1640 medium with 10% FBS. Several final concentrations of macrolide antibiotics (4 concentrations of each antibiotic) were used in the following experimen...

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“…20 Other macrolides such as erythromycin have been shown to inhibit hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium, as well as inhibit the proliferation of human mononuclear cells. 21,22 Azithromycin along with clarithromycin are reported to induce apoptosis of activated lymphocytes. 23 In previous studies in our laboratory, azithromycin was also observed to cause reversible autophagy in rabbit tracheal SMCs, but not apoptosis, as well as reversible inhibition of the proliferation.…”

Section: Discussionmentioning

confidence: 99%

Azithromycin reduces the viability of human bronchial smooth muscle cells

et al. 2010

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The macrolide antibiotic azithromycin has an antiproliferative and autophagic effect on rabbit tracheal smooth muscle cells (SMCs). The purpose of this study is to investigate the effect of azithromycin on human bronchial SMCs. Human bronchial SMCs were treated with azithromycin (10 À5 M) in the presence or absence of 10% fetal bovine serum (FBS). Cell number was estimated using the Cell Titer 96 AQ ueous One Solution Assay. Induction of autophagy was studied by observation of cell morphology in cells treated or not with the autophagy inhibitor, 3-methyladenine (3-MA), as well as by Lysotracker Red staining of lysosomes. Activation of apoptosis was assessed with flow cytometry after annexin staining. Incubation with azithromycin for 24, 48 or 72 h reduced viability in FBS-deprived cells, as well as cells cultured in FBS-containing medium. Azithromycin treatment resulted in the formation of cytoplasmic vacuoles that could not be prevented by 3-MA. Furthermore, 3-MA did not reverse the effect of azithromycin on the viability of SMCs. There was an increase in the number of lysosomes in cells treated with azithromycin. Finally, azithromycin increased the percentage of early apoptotic cells. In conclusion, azithromycin reduces the viability of human bronchial SMCs possibly by leading to apoptotic cell death.

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Macrolides and immunity: effects of erythromycin and spiramycin on human mononoclear cell proliferation

Cited by 52 publications

References 0 publications

Differential modulation of cytokine production by macrolides: interleukin-6 production is increased by spiramycin and erythromycin

Differential modulation of cytokine production by macrolides: interleukin-6 production is increased by spiramycin and erythromycin

Effect of Macrolide Antibiotics on Macrophage Functions

Azithromycin reduces the viability of human bronchial smooth muscle cells

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