Activation of the innate immune system involves a series of events designed to counteract the initial insult followed by the clearance of debris and promotion of healing. Aberrant regulation can lead to systemic inflammatory response syndrome, multiple organ failure, and chronic inflammation. A better understanding of the innate immune response may help, manage complications while allowing for proper immune progression. In this study, the ability of several classes of anti-inflammatory drugs to affect LPS-induced cytokine and prostaglandin release from peripheral blood mononuclear cells (PBMC) was evaluated. PBMC were cultured in the presence of dexamethasone (DEX), ibuprofen (IBU), and the low molecular weight fraction of 5% albumin (LMWF5A) followed by stimulation with LPS. After 24 h, TNF alpha, PGE(2), and 15d-PGJ(2) release was determined by ELISA. Distinct immunomodulation patterns emerged following LPS stimulation of PBMC in the presence of said compounds. DEX, a steroid with strong immunosuppressive properties, reduced TNF alpha, PGE(2), and 15d-PGJ(2) release. IBU caused significant reduction in prostaglandin release while TNFa release was unchanged. An emerging biologic with known anti-inflammatory properties, LMWF5A, significantly reduced TNF alpha release while enhancing PGE(2) and 15d-PGJ(2) release. Incubating LMWF5A together with IBU negated this observed increased prostaglandin release without affecting the suppression of TNF alpha release. Additionally, LMWF5A caused an increase in COX-2 transcription and translation. LMWF5A exhibited a unique immune modulation pattern in PBMC, disparate from steroid or NSAID administration. This enhancement of prostaglandin release (specifically 15d-PGJ(2)), in conjunction with a decrease in TNF alpha release, suggests a switch that favors resolution and decreased inflammation. (C) 2016 Elsevier Inc. All rights reserved.