LMWF5A Demonstrates an Anti-Inflammatory Mode of Action and Similar Drug Targets to Dexamethasone in Activated PBMC
Abstract The low molecular weight fraction of human serum albumin (LMWF5A) has proven immunomodulatory activity via its effects on multiple inflammatory mediators and transcription factors. This biologic drug is currently being evaluated for the treatment of conditions characterized by hyperactive or persistent immune responses. To gain further insight into the mechanism of action of LMWF5A, an unbiased investigation of its effects on activated immune cells was performed. Peripheral blood mononuclear cells (PBMC) were treated with vehicle control or LMWF5A and stimulated with lipopolysaccharide (LPS), LPS/interferon g, or interleukin (IL)-4/IL-13 for 24h. Differential gene expression analysis by RNAseq was performed to determine transcriptional changes due to LMWF5A treatment in each stimulation condition. Ingenuity Pathway Analysis software was employed to reveal overall biological trends observed in the RNAseq datasets and to identify compounds with comparable or contrasting activities to LMWF5A. Analysis of each RNA dataset revealed broad anti-inflammatory and pro-resolving activities for LMWF5A, with predicted inhibition of key pro-inflammatory mediators and functions as well as activation of some anti-inflammatory mediators. Upstream regulator analysis confirmed these activities and identified the corticosteroid dexamethasone as the most significantly similar regulator. Further comparison of LMWF5A and dexamethasone revealed similar, but not identical, targets and directional regulation. This study supports our current knowledge on the mode of action of LMWF5A and provides new hypotheses for future investigations. Due to its analogous biological effects with dexamethasone and known safety profile, LMWF5A may be used to treat conditions that are supported for dexamethasone with fewer or less harmful side effects.