Review
Anti-inflammatory effects of macrolide antibiotics

https://doi.org/10.1016/S0014-2999(01)01321-8Get rights and content

Abstract

Macrolides are widely used as antibacterial drugs. Clinical and experimental data, however, indicate that they also modulate inflammatory responses, both contributing to the treatment of infective diseases and opening new opportunities for the therapy of other inflammatory conditions. Considerable evidence, mainly from in vitro studies, suggests that leukocytes and neutrophils in particular, are important targets for modulatory effects of macrolides on host defense responses. This underlies the use of the 14-membered macrolide erythromycin for the therapy of diffuse panbronchiolitis. A variety of other inflammatory mediators and processes are also modulated by macrolides, suggesting that the therapeutic indications for these drugs may be extended significantly in future.

Introduction

Macrolides are a well-established family of antibiotics isolated from streptomycetes. Their main characteristic is a macrocyclic lactone ring with one or two sugar moieties. They experienced a renaissance during the 1980s and 1990s, in which the commercial introduction of several semi-synthetic derivatives significantly expanded their therapeutic importance and utility. Among the most important characteristics of the macrolide antibiotics are a moderately broad spectrum of antibacterial activity, activity by oral administration and a relatively high therapeutic index. The first macrolide introduced into clinical practice was the 14-membered ring compound—erythromycin A. It was isolated from cultures of Streptomyces erythraea in 1952 (Washington et al., 1985; for review, see Mazzei et al., 1993, Williams and Sefton, 1993). The 15-membered macrolide antibiotic, azithromycin (a representative of the so-called azalides), has now become one of the most widely prescribed of all antibiotics. Macrolides like tylosine are widely used in veterinary medicine. The most recently synthesized macrolides are in late phase clinical development or approved for clinical use (e.g., the ketolides, ABT-773 and telithromycin). They are called ketolides because instead of sugar (l-cladinosyl moiety) at position 3 of the lactone ring these antibiotics have a keto-group (Wu, 2000). The principle advantage of this series of compounds is their activity against macrolide-resistant streptococci (Resek et al., 2000). For a recent review on anti-infective aspects of macrolides and particularly ketolides see Zhanel et al. (2001).

Structures of the most commonly used antibiotics are shown in Fig. 1. In addition to the chemical (semi-synthetic) approach to the development of new macrolide antibiotics, an alternative approach employing molecular biology techniques has also been used. Biotechnology permits the modification and interchange of specific parts of various biosynthetic gene clusters, like polyketide synthase, to produce new macrolide structures (Katz and Donadio, 1993). This process of artificial natural product formation is called recombinant biosynthesis Tsoi et al., 1995, Katz and McDaniel, 1999.

The mechanism of macrolide antibiotic action is based on inhibition of bacterial protein synthesis, by interacting with 23S rRNA in the central loop of the peptidyltransferase center as well as with specific ribosomal proteins found in the same region of the ribosome. Macrolides are best known as anti-infectives but also exert other important pharmacological effects such as immunosuppression and immunomodulation. For example, FK506 (tacrolimus) is a highly effective immunosuppressive drug used in organ transplantation and is one of the best immunosuppressive drugs available. This 23-membered macrolide lactone binds to FKBP 12 and modulates the calcineurin pathway. At subnanomolar concentrations it was shown to inhibit the proliferation of T cells stimulated by specific antigens (for review, see Dumont, 2000). Rapamycin (31-membered ring macrolide), although belonging to the same chemical class causes immunosuppression by a different mechanism. It forms an immunophilin complex that does not bind calcineurin and is therefore devoid of the calcineurin-related effects seen with FK506. Rapamycin was recently shown to inhibit apoptosis in human HL-60 cells (Johnson and Lawen, 1999).

Bafilomycin (16-membered macrolide) and concanamycin (18-membered macrolide) are the most potent specific inhibitors of vacuolar type H+-ATPase (for reviews, see Droese and Altendorf, 1997, Keeling et al., 1997, Gagliardi et al., 1999). Inhibition of the vacuolar H+-ATPase indirectly causes apoptotic cell death (Nishihara et al., 1995). Moreover, an intracellular apoptosis-inducing factor with a molecular mass of 33 kDa seems to be induced by concanamycin A treatment of (hybridoma) cells (Hashimoto et al., 2001). Oligomycin and apoptolidin are potent inhibitors of ATP-synthetase (F0F1-ATPase) and are among the most cytotoxic drugs for malignant cells Salomon et al., 2000, Salomon et al., 2001. There are also other scattered reports on macrolide actions which could not be classified as anti-bacterial, e.g. gastrointestinal motor stimulating activity (Omura et al., 1987), anti-cancer (Hamada et al., 2000) and anti-angiogenic effects Yatsunami et al., 1999a, Yatsunami et al., 1999b. Among the most peculiar ones are an anorexigenic reaction associated with weight loss (proposed for obesity treatment) and reduction of serum triglyceride levels with simultaneous increase in serum high-density lipoprotein (HDL) levels Klein, 1996, Klein, 2001.

In many cases, biological targets of macrolides remain unknown and still not sufficiently exploited. The techniques of proteomics and genomics could help to systematically explore targets with which various macrolides are capable of interacting (genes and/or proteins).

The main topic of this review is macrolides that influence targets of relevance for inflammatory processes. This is not a new topic and several excellent reviews have been written about these effects Gemmell, 1993, Wales and Woodhead, 1999, Labro, 1998a, Labro, 1998b, Rubin and Tamaoki, 2000, Labro, 2000, Labro and Abdelghaffar, 2001. The purpose of this review is to emphasize the most interesting newer findings, especially those that reveal the neutrophil as an important cellular target of macrolide action.

Section snippets

Inflammation

Most inflammatory diseases whether infective or non-infective in origin, are characterized by abnormal accumulation of inflammatory cells (including monocytes, macrophages, granulocytes, plasma cells, lymphocytes and platelets) that along with tissue endothelial cells and fibroblasts, release a complex array of lipid mediators, growth factors, cytokines and destructive enzymes that cause local tissue damage. Tissue damage in a group of neutrophil-dominated inflammatory diseases (bacterial

Cellular pharmacokinetics of macrolides

Additional interest in the therapeutic use of macrolide antibiotics has been based on the demonstration of their ability to concentrate within phagocytes. Macrolide antibiotics show unique and favorable cellular pharmacokinetic properties. The concentrations of azithromycin and clarithromycin, for instance, in the epithelial lung fluid normally tend to be at least 10-fold greater than simultaneously measured concentrations in the plasma or serum. These high concentrations often exceed the

Anti-inflammatory and other in-vitro effects of macrolides

A considerable body of evidence on in vitro effects of macrolides is present in the scientific literature. Nevertheless, these reports are sometimes contradictory. At least partially, the contradictions can be resolved by taking into account often very different experimental conditions (for review, see Labro and El Benna, 1993). Macrolide antibiotics modulate the functions of inflammatory cells, such as polymorphonuclear leukocytes, lymphocytes and macrophages Anderson, 1989, Roche et al., 1986

Healthy animals

There appear to be some differences between the effects of macrolides on inflammatory models and their effects on potentially inflammatory parameters in healthy animals. In the healthy guinea pig, roxithromycin increased airway ciliary activity after 14 days of oral administration. In addition, neutrophils in these animals exhibited increased superoxide production but their phagocytic activity remained unchanged (Sugiura et al., 1997). Ex vivo, it was shown that in healthy mice, a 28-day (but

Molecular targets of anti-inflammatory macrolides

In a recent milestone report (Aoki and Kao, 1999) erythromycin in vitro was shown to inhibit activation of the transcription factor NF-κB through a calcineurin-independent pathway. This is one of the first successful attempts to define the anti-inflammatory targets of the macrolide antibiotics at the molecular level. In a reporter gene assay, erythromycin at a concentration of 10−5 M inhibited interleukin-8 NF-κB transcription by 37%. It remains unclear whether the basis for inhibition lies in

Diffuse panbronchiolitis

In contrast to the large numbers of in vitro studies on anti-inflammatory effects of macrolide antibiotics, only a very limited number of clinical trials have been reported, and few in-vivo studies deal with the anti-inflammatory potential of macrolides. Some macrolide antibiotics like erythromycin, clarithromycin and roxithromycin have already been used as anti-inflammatory drugs, especially for the treatment of diffuse panbronchiolitis. Reports on the use of macrolides for diseases like

Conclusions

Over many years, macrolides have proven to be very effective antibacterial agents. Clinical and experimental data now indicate that the effects of macrolides are not just restricted to direct action on bacteria, but also involve modulation of host defense mechanisms. Phagocytes in particular appear to be important targets for macrolides. This is indicated by a decade of use of erythromycin in clinical treatment of diffuse panbronchiolitis. Effects of macrolides on host defense mechanism and/or

Acknowledgments

We would like to thank K. Brajša, V. Munić, W. Schönfeld and D. Verbanac for critical reading of the manuscript. We also thank M. Bosnar, S. Alihodžić and S.K. Kujundžić for their help in the preparation of the manuscript.

References (234)

  • H. Abdelghaffar et al.

    Comparison of various macrolides for stimulation of human neutrophil degranulation

    J. Antimicrob. Chemother.

    (1996)
  • H. Abdelghaffar et al.

    Erythromycin A-derived macrolides modify the functional activities of human neutrophils by altering the phospholipase d-phosphatide phosphohydrolase transduction pathway. l-Cladinose is involved both in alteration of neutrophil function and modulation of this transductional pathway

    J. Immunol.

    (1997)
  • S. Abe et al.

    Interleukin-8 gene repression by clarithromycin is mediated by the activator protein-1 binding site in human bronchial epithelial cells

    Am. J. Respir. Cell Mol. Biol.

    (2000)
  • C. Agen et al.

    Macrolide antibiotics as anti-inflammatory agents: roxithromycin in an unexpected role

    Agents Actions

    (1993)
  • Amsden, G.W., Gray, C.L., 2001. Serum and WBC pharmacokinetics of 1500 mg of azithromycin when given either as a single...
  • R. Anderson

    Erythromycin and roxithromycin potentiate human neutrophil locomotion in vitro by inhibition of leukoattractant-derived superoxide generation and auto-oxidation

    J. Infect. Dis.

    (1989)
  • J.L. Anderson et al.

    Randomized secondary prevention trial of azithromycin in patients with coronary artery disease and serological evidence for Chlamydia pneumoniae infection: the Azithromycin in Coronary Artery Disease: elimination of Myocardial Infection with Chlamydia (ACADEMIC) study

    Circulation

    (1999)
  • Y. Aoki et al.

    Erythromycin inhibits transcriptional activation of NF-kappaB, but not NFAT, through calcineurin-independent signaling in T cells

    Antimicrob. Agents Chemother.

    (1999)
  • K. Aoshiba et al.

    Erythromycin shortens neutrophil survival by accelerating apoptosis

    Antimicrob. Agents Chemother.

    (1995)
  • T. Arayssi

    Is there a role for macrolides in arthritis?

  • D.A. Arenberg et al.

    Inhibition of interleukin-8 reduces tumorigenesis of human non-small cell lung cancer in SCID mice

    J. Clin. Invest.

    (1996)
  • J.W. Athens et al.

    Leukokinetic studies: III. The distribution of granulocyte in the blood of normal subjects

    J. Clin. Invest.

    (1961)
  • J.W. Athens et al.

    Leukokinetic studies: IV. The total blood, circulating and marginal granulocyte pools and the granulocyte turnover rate in normal subjects

    J. Clin. Invest.

    (1961)
  • P.C. Avilla et al.

    Macrolides, asthma, inflammation and infection

    Ann. Allergy Asthma Immunol.

    (2000)
  • S. Bailly et al.

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

    Antimicrob. Agents Chemother.

    (1991)
  • S. Bailly et al.

    Effects des antibiotiques sur la production de cytokines par les monocytes humains

    Pathol. Biol.

    (1993)
  • R. Baisakhi et al.

    Nitric oxide blocks nuclear factor-κB activation in alveolar macrophages

    Am. J. Respir. Cell Mol. Biol.

    (1999)
  • D.T. Bearden et al.

    Penetration of macrolides into pulmonary sites of infections

    Infect. Med.

    (1999)
  • L.E. Bermudez et al.

    Stimulation with cytokines enhances penetration of azithromycin into human macrophages

    Antimicrob. Agents Chemother.

    (1991)
  • M. Bonnet et al.

    In vitro and in vivo interleukocytic accumulation of azithromycin (CP-62, 993) and its influence on ex vovo leukocyte chemiluminescence

    Antimicrob. Agents Chemother.

    (1992)
  • P.C. Braga et al.

    Effects of rokitamycin on phagocytosis and release of oxidant radicals of human polymorphonuclear leukocytes

    Chemotherapy

    (1997)
  • S. Brennan et al.

    Direct neutrophil migration to IL-8 is increased in cystic fibrosis: a study of the effect of erythromycin

    Thorax

    (2001)
  • D. Brull et al.

    Infection, inflammation and coronary artery disease: more than just an association?

    Br. J. Cardiol.

    (2000)
  • O. Carević et al.

    Comparative studies on the effects of erythromycin A and azithromycin upon extracellular release of lysosomal enzymes in inflammatory processes

    Agents Actions

    (1988)
  • M.B. Carlier et al.

    Cellular uptake and subcellular distribution of roxithromycin and erythromycin in phagocytic cells

    J. Antimicrob. Chemother.

    (1987)
  • M.B. Carlier et al.

    Accumulation, release and subcellular localization of azithromycin in phagocytic and non-phagocytic cells in culture

    Int. J. Tissue React.

    (1994)
  • M. Cazolla et al.

    Potential role of macrolides in the treatment of asthma

    Monaldi Arch. Chest Dis.

    (2000)
  • A. Cervin

    The anti-inflammatory effect of erythromycin and its derivatives: special reference to nasal polyposis and chronic sinusitis

    Acta Otolaryngol.

    (2001)
  • E.R. Chilvers et al.

    Regulation of granulocyte apoptosis and implication for anti-inflammatory therapy

    Thorax

    (1998)
  • A.C. Chin et al.

    Tilmicosin induces apoptosis in bovine peripheral neutrophils in the presence or in absence of Pasteurella hemolytica and promotes neutrophil phagocytosis by macrophages

    Antimicrob. Agents Chemother.

    (2000)
  • G.I. Criqui et al.

    Effects of azithromycin on ozone-induced airway neutrophil and cytokine release

    Eur. Respir. J.

    (2000)
  • F. D'Acqisto et al.

    Local administration of transcription factor decoy oligonucleotides to nuclear factor-kappa B prevents carrageenin-induced inflammation in rat hind paw

    Gene Ther.

    (2000)
  • S. Droese et al.

    Bafilomycins and concanamycins as inhibitors of V-ATPases and P-ATPases

    J. Exp. Biol.

    (1997)
  • F.J. Dumont

    FK506, an immunosuppressant targeting calcineurin function

    Curr. Med. Chem.

    (2000)
  • A.L. Dunican et al.

    TNF-alpha-induced suppression of polymorphonuclear leukocyte apoptosis is mediated through interleukin-8 production

    Shock

    (2000)
  • J. Dunlay et al.

    A placebo-controlled, double-blind trial of erythromycin in the treatment of acute bronchitis

    J. Fam. Pract.

    (1987)
  • M.W. Dunne

    Rationale and design of a secondary prevention trial of antibiotic use in patients after myocardial infarction: the WIZARD (weekly intervention with zithromax (azithromycin) for atherosclerosis and its related disorders) trial

    J. Infect. Dis.

    (2000)
  • M. Duong et al.

    Immunomodulating effects of HMR 3004 on pulmonary inflammation caused by heat-killed Streptococcus pneumoniae in mice

    Antimicrob. Agents Chemother.

    (1998)
  • J.M. Duran et al.

    Azithromycin: indications for the future?

    Expert Opin. Pharmacother.

    (2000)
  • F. Enomoto et al.

    Evaluation of the effect of erythromycin on otitis media with effusion in experimental rat models

    Nippon Jibiinkoka Gakkai Kaiho

    (1996)
  • Cited by (290)

    • Macrolides for Rhinosinusitis and Nasal Polyps

      2024, Progress in Inflammation Research
    • Macrolides and Cystic Fibrosis

      2024, Progress in Inflammation Research
    View all citing articles on Scopus
    View full text