Suppression of endotoxin release and subsequent production of inflammatory cytokines is crucial in the treatment of septic shock. We investigated the effect of clindamycin (CLI) on endotoxic shock induced in mice by Escherichia coli lipopolysaccharide (LPS). Mice were treated with CLI (160 to 600 mg/kg) or saline and then injected with E. coli LPS and D-(؉)-galactosamine intraperitoneally 0.5 h after CLI administration. Pretreatment with CLI significantly improved survival in a dose-dependent manner (CLI, at 160, 300, and 440 mg/kg) and significantly lowered the peak concentrations of tumor necrosis factor alpha and interleukin-1␤ (IL-1␤) in serum. However, the peak concentrations of IL-6 in the sera of CLI-treated mice were higher than in control mice. Our findings suggest that CLI alters LPS-induced inflammatory cytokine production and suppresses endotoxin-induced mortality in this murine model.

We investigated the mechanism by which clindamycin (CLI) modulates cytokine induction after lipopolysaccharide (LPS) stimulation. Although CLI decreased the intracellular expression levels of tumor necrosis factor alpha and interleukin 1␤ (IL-1␤) and increased IL-6 expression in macrophages, cytokine mRNA expression levels were similar in CLI-treated and untreated groups. Our findings suggest that CLI modulates cytokine production in LPS-stimulated macrophages.Anticytokine effects, which are independent of their antibacterial properties, have been reported elsewhere for several antimicrobial agents (2, 7, 9). Furthermore, these anticytokine effects on inflammatory cytokines have been studied at a molecular level (12,14,16). It was recently reported that clindamycin (CLI) reduces tumor necrosis factor alpha (TNF-␣) concentrations in lipopolysaccharide (LPS)-stimulated THP-1 cells (8) and that CLI decreases TNF-␣ and interleukin 1␤ (IL-1␤) concentrations and increases serum IL-6 concentrations, as well as reducing mortality in the mouse model (4). The present study showed the mechanism of modulation by CLI of inflammatory-cytokine production by LPS-stimulated macrophages, both in vitro and in vivo.Two milliliters of 4% thioglycolate fluid medium (Difco, Detroit, Mich.) was intraperitoneally injected into 10-week-old C3H/HeN male mice. After 4 days peritoneal lavage fluid was collected and cultured on plastic plates in Iscove's modified Dulbecco's medium supplemented with 10% heat-inactivated fetal bovine serum at 37°C under 5% CO 2 for 90 min. Adherent cells were used as the macrophages (esterase staining confirmed that 95%

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