Publication Date:
2019
Description:
〈p〉Vaccine adjuvants containing analogs of microbial products activate pattern recognition receptors (PRRs) on antigen-presenting cells, including monocytes and macrophages, which can cause prostaglandin E〈sub〉2〈/sub〉 (PGE〈sub〉2〈/sub〉) release and consequently undesired inflammatory responses and fever in vaccine recipients. Here, we studied the mechanism of PGE〈sub〉2〈/sub〉 production by human monocytes activated with muramyl dipeptide (MDP) adjuvant, which activates cytosolic nucleotide-binding oligomerization domain 2 (NOD2). In rabbits, administration of MDP elicited an early increase in PGE〈sub〉2〈/sub〉 followed by fever. In human monocytes, MDP alone did not induce PGE〈sub〉2〈/sub〉 production. However, high amounts of PGE〈sub〉2〈/sub〉 and the proinflammatory cytokines IL-1β and IL-6 were secreted by monocytes activated with MDP in the presence of conditioned medium obtained from CD3 bead–isolated T cells (Tc CM) but not from those isolated without CD3 beads. Mass spectrometry and immunoblotting revealed that the costimulatory factor in Tc CM was glycoprotein Ib α (GPIbα). Antibody-mediated blockade of GPIbα or of its receptor, Mac-1 integrin, inhibited the secretion of PGE〈sub〉2〈/sub〉, IL-1β, and IL-6 in MDP + Tc CM–activated monocytes, whereas recombinant GPIbα protein increased PGE〈sub〉2〈/sub〉 production by MDP-treated monocytes. In vivo, 〈i〉COX2〈/i〉 mRNA abundance was reduced in the liver and spleen of Mac-1 KO mice after administration of MDP compared with that of treated wild-type mice. Our findings suggest that the production of PGE〈sub〉2〈/sub〉 and proinflammatory cytokines by MDP-activated monocytes is mediated by cooperation between two signaling pathways: one delivered by MDP through NOD2 and a second through activation of Mac-1 by T cell–derived GPIbα.〈/p〉
Print ISSN:
1945-0877
Electronic ISSN:
1937-9145
Topics:
Biology
,
Medicine
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