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

Abstract

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.

Clindamycin Modulates Inflammatory-Cytokine Induction in Lipopolysaccharide-Stimulated Mouse Peritoneal Macrophages

“…Our in vitro studies revealed that CLI dose-dependently decreased TNF-␣ and IL-1␤ production and increased IL-6 production by macrophages. These results are similar to those obtained in in vitro studies where LPS-stimulated human monocytes were treated with fosfomycin (11) and erythromycin (1,5). In addition to the in vitro results, we confirmed that, in vivo, CLI modulated the induction of inflammatory cytokines through its action on peritoneal macrophages as one of the target cells.…”

Characterization of peripheral blood T-lymphocytes transduced with HTLV-I Tax mutants with different trans-activating phenotypes

“…Di erences in the level of several cytokines in the culture supernatant from wild-type Tax1 expressing PBL and mutant 703 expressing PBL was detected prior to the appearance of signi®cant di erence in the CD4+ cell population (Akagi et al unpublished data). In this context, it is worth mentioning that many Taxinducible cytokine genes have motifs of CRE or AP-1, which are activated indirectly by SRF, in combination with NF-kB in the promoter region (Bailly et al, 1996;Curtiss et al, 1996;Himes et al, 1993;Mori and Prager, 1996;Mori et al, 1994b;Yamashita et al, 1994). Full activation of these cytokine gene promoters might only be achieved by wild-type Tax1.…”

Efficacy of erythromycin lactobionate for treating Pseudomonas aeruginosa bacteremia in mice

“…With regard to IL-1, it is known that this cytokine increases the survival rate of mice systemically infected with P. aeruginosa (21). Recently, Bailly et al have reported that EM increased IL-6 production by human monocytes in vitro (4). Therefore, it is possible that EM possesses a lot of immunopotentiating effects, including the enhancement of cytokines production, and subsequently enhances the host defense system.…”