Erythromycin inhibits tumor necrosis factor alpha and interleukin 6 production induced by heat-killed Streptococcus pneumoniae in whole blood

Abstract

To determine the effects of penicillin and erythromycin on cytokine production induced by heat-killed Streptococcus pneumoniae (HKSP), we studied the effects of those drugs on cytokine production induced by S. pneumoniae in human whole blood in vitro and ex vivo. In whole blood in vitro, erythromycin, but not penicillin, caused a dose-dependent decrease in HKSP-induced production of tumor necrosis factor alpha (TNF) and interleukin 6 (IL-6), while the production of IL-10, IL-12, and gamma interferon was inhibited only at the highest erythromycin concentration tested (10(-3) M). The production of TNF and IL-6 in whole blood obtained from healthy subjects after a 30-min infusion of erythromycin (1,000 mg) was lower after ex vivo stimulation with HKSP than that in blood drawn before the infusion. Inhibition of TNF contributed to erythromycin-induced inhibition of IL-6 synthesis. Inhibition of TNF and IL-6 production by erythromycin may have a negative impact on host defense mechanisms during pneumococcal pneumonia.

FIG. 1

Time-dependent release of TNF, IL-10, IL-6, IFN-γ, IL-12 p40, and IL-12 p70 in HKSP-stimulated blood. Whole blood diluted 1:1 in sterile RPMI 1640 was stimulated for 4 to 24 h at 37°C with HKSP (•, 10⁷ CFU/ml; ○, 10⁶ CFU/ml). Data are means ± standard errors of the means for six healthy donors.

FIG. 2

Erythromycin, but not penicillin, influences the release of TNF, IL-10, IL-6, IFN-γ, IL-12 p40, and IL-12 p70 in HKSP-stimulated whole blood. Whole blood diluted 1:1 in sterile RPMI 1640 was stimulated for 16 h at 37°C with HKSP (10⁷ CFU/ml) and erythromycin (•) or penicillin (○) (both at concentrations of 10⁻⁵ to 10⁻³ M). Values are expressed relative to production in the absence of penicillin and erythromycin (means ± SEs for six healthy donors). ∗, P < 0.05 versus value obtained after incubation without erythromycin. Concentrations after stimulation without penicillin (set at 100%) were 34.1 ± 5.2 ng/ml for TNF, 2.8 ± 0.5 ng/ml for IL-10, 75.7 ± 11.3 ng/ml for IL-6, 4.0 ± 1.6 ng/ml for IFN-γ, 2.1 ± 0.4 ng/ml for IL-12 p40, and 43 ± 21 pg/ml for IL-12 p70.

FIG. 3

Erythromycin infusion inhibits the production of TNF and IL-6. Six healthy volunteers each received a 30-min intravenous infusion of 1,000 mg of erythromycin in 250 ml of 0.9% NaCl (hatched bar). Blood was collected directly before and directly after infusion and at 1, 2, and 4 h after the end of infusion. Whole blood diluted 1:1 in sterile RPMI 1640 was stimulated for 16 h at 37°C with HKSP (10⁷ CFU/ml). Values are expressed relative to production before infusion of erythromycin (mean ± SEs for six healthy donors). Concentrations after stimulation and before infusion of erythromycin (set at 100%) were 18.4 ± 1.7 ng/ml for TNF and 165.8 ± 24.4 ng/ml for IL-6. ∗, P < 0.05 versus value obtained before infusion of erythromycin.