Control of human inflammatory cell responses by prostaglandins and related metabolites

Inflammation is an essential component of the innate immune system and is crucial for protecting against bacterial infection. The stimulation of human inflammatory cells by bacterial LPS triggers the production of pro-inflammatory cytokines, especially TNF-α, which perpetuate this response. Monocytes produce these primary mediators of inflammation in abundance and are thus highly important inflammatory cells. The production of cytokines such as TNF-α leads to the biosynthesis of secondary mediators of inflammation, specifically prostaglandins, which are lipid-derived mediators that initiate the physiological changes responsible for the symptoms of inflammation. Prostaglandins also play an immunomodulatory role within the inflammatory response by suppressing the production of pro-inflammatory cytokines particularly TNF-α. This suppression occurs in a negative feedback regulatory manner in the late stages of infection suggesting a role for prostaglandins in the resolution of inflammation. Such resolution is vital as chronic inflammation can cause significant damage to healthy tissues. The project therefore studied the immunomodulatory effect of the prostaglandin D2 metabolite, 15d-PGJ2, on human monocytic cell activities specifically the production of TNF-α in response to bacterial LPS. This involved the growth and culture of the human monocytic cell line, THP-1, and use of a human TNF-α ELISA system. Mechanistic studies investigated the specific receptor and signalling pathways mediating this effect by utilising pharmacological agents that interfere with these systems. The study surmised that 15d-PGJ2 was able to downregulate the production of TNF-α in human monocytes following LPS stimulation and that this suppression appears to occur via Gi-signalling involving the DP2 prostanoid receptor. Further targeted investigations into the pathways that mediate the suppressive actions of 15d-PGJ2 may therefore reveal a novel therapeutic intervention for inflammatory conditions.Inflammation is an essential component of the innate immune system and is crucial for protecting against bacterial infection. The stimulation of human inflammatory cells by bacterial LPS triggers the production of pro-inflammatory cytokines, especially TNF-α, which perpetuate this response. Monocytes produce these primary mediators of inflammation in abundance and are thus highly important inflammatory cells. The production of cytokines such as TNF-α leads to the biosynthesis of secondary mediators of inflammation, specifically prostaglandins, which are lipid-derived mediators that initiate the physiological changes responsible for the symptoms of inflammation. Prostaglandins also play an immunomodulatory role within the inflammatory response by suppressing the production of pro-inflammatory cytokines particularly TNF-α. This suppression occurs in a negative feedback regulatory manner in the late stages of infection suggesting a role for prostaglandins in the resolution of inflammation. Such resolution is vital as chronic inflammation can cause significant damage to healthy tissues. The project therefore studied the immunomodulatory effect of the prostaglandin D2 metabolite, 15d-PGJ2, on human monocytic cell activities specifically the production of TNF-α in response to bacterial LPS. This involved the growth and culture of the human monocytic cell line, THP-1, and use of a human TNF-α ELISA system. Mechanistic studies investigated the specific receptor and signalling pathways mediating this effect by utilising pharmacological agents that interfere with these systems. The study surmised that 15d-PGJ2 was able to downregulate the production of TNF-α in human monocytes following LPS stimulation and that this suppression appears to occur via Gi-signalling involving the DP2 prostanoid receptor. Further targeted investigations into the pathways that mediate the suppressive actions of 15d-PGJ2 may therefore reveal a novel therapeutic intervention for inflammatory conditions