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Sophorolipids, a family of natural and easily chemoenzymatically modified microbial glycolipids, are promising modulators of the immune response. The potential of the therapeutic effect of sophorolipids was investigated in vivo in a rat model of sepsis and in vitro by analysis of nitric oxide and cytokine production.Prospective, randomized animal study.Experimental laboratory.Male Sprague-Dawley rats, 200–240 g.Intra-abdominal sepsis was induced in vivo in 166 rats via cecal ligation and puncture (CLP); 60 rats were used to characterize the model. The remaining rats were treated with sophorolipids or vehicle (dimethylsulfoxide [DMSO]/physiologic saline) by intravenous (iv) tail vein or intraperitoneal (IP) injection immediately post-CLP (25/group). Survival rates were compared at 36 hrs after surgery. In vitro, macrophages were cultured in lipopolysaccharide (LPS) ± sophorolipid and assayed for nitric oxide (NO) production and gene expression profiles of inflammatory cytokines. In addition, splenic lymphocytes isolated from CLP rats ± sophorolipid treatment (three per group) were analyzed for cytokine production by RNase protection assay.CLP with 16-gauge needles optimized sepsis induction and resultant mortality. Sophorolipid treatment improved rat survival by 34% (iv) and 14% (IP) in comparison with vehicle controls (p < .05 for iv treatment). Sophorolipids decreased LPS-induced macrophage NO production by 28% (p < .05). mRNA expression of interleukin (IL)-1β was downregulated by 42.5 ± 4.7% (p < .05) and transforming growth factor (TGF)-β1 was upregulated by 11.7 ± 1.5% (p < .05) in splenocytes obtained 6 hrs postsophorolipid treatment. LPS-treated macrophages cultured 36 hrs with sophorolipids showed increases in mRNA expression of IL-1α (51.7%), IL-1β (31.3%), and IL-6 (66.8%) (p < .05).Administration of sophorolipids after induction of intra-abdominal sepsis significantly decreases mortality in this model. This may be mediated in part by decreased macrophage NO production and modulation of inflammatory responses.