Abstract
Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator that contains a unique cyclic phosphate ring at the sn-2 and sn-3 positions of its glycerol backbone. Using mouse models for multiple sclerosis (cuprizone-induced demyelination and experimental autoimmune encephalomyelitis) and traumatic brain injury, we revealed that cPA and its metabolically stabilized cPA derivative, 2-carba-cPA (2ccPA), have potential to protect against neuroinflammation. In this study, we investigated whether 2ccPA has anti-inflammatory effect on peripheral immune function or not using inflammation-induced macrophages-like cell line, THP-1 monocytes differentiated by phorbol 12-myristate 13-acetate (PMA). Lipopolysaccharide (LPS)-stimulated THP-1 cells were found to have higher expression of the mRNAs of several inflammation-related cytokines and of the enzyme cyclooxygenase-2 (Cox-2); however, when THP-1 cells were stimulated by LPS in the presence of 2ccPA, the increase in the expression of pro-inflammatory cytokine and Cox-2 mRNA was attenuated. 2ccPA treatment also decreased the amount of prostaglandin E2 (PGE2) produced by LPS-stimulated THP-1 cells and decreased expression of the mRNA of prostaglandin E receptor 2 (EP2, PTGER2), a PGE2 receptor that mediates inflammation. These results indicate that 2ccPA has anti-inflammatory properties.
Highlights
Macrophages play important roles in the host defense system via the phagocytosis and release of inflammation-associated enzyme and various cytokines, such as pro- and anti-inflammatory cytokines [1,2]
To gain insight into the anti-inflammatory function of 2ccPA upon exposure to infectious stimuli, we investigated the effect of 2ccPA on cytokines and Cox-2 mRNA expression using a lipopolysaccharide (LPS)-stimulated human macrophage cell line
Because CD11b expression was increased in PMAtreated THP-1 cells (Fig. 1A and B), we used these adherent cells as being representative of human macrophage for subsequent experiments
Summary
Macrophages play important roles in the host defense system via the phagocytosis and release of inflammation-associated enzyme (cyclooxygenase-2, Cox-2) and various cytokines, such as pro- (interleukin [IL]-1β, IL-6, tumor necrosis factor [TNF]-α) and anti-inflammatory cytokines (transforming growth factor [TGF]-β) [1,2]. We surmise that attenuating the expression of Cox-2 and pro-inflammatory cytokines in activated macrophages could relieve inflammation. We previously reported that cPA attenuates neuropathic pain and neuroinflammation [11,12]. These results suggested that cPA could be a therapeutic compound for these diseases. 2ccPA reduced the damage associated with traumatic brain injury (TBI) induced using stab wound surgery with vertical needle injury and suppressed the expression of pro-inflammatory cytokines To gain insight into the anti-inflammatory function of 2ccPA upon exposure to infectious stimuli, we investigated the effect of 2ccPA on cytokines and Cox-2 mRNA expression using a lipopolysaccharide (LPS)-stimulated human macrophage cell line. We examined the effect of 2ccPA on arachidonic cascade and found that 2ccPA has regulatory effect on the production of members of the arachidonic cascade
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