T cell-derived soluble glycoprotein GPIbα mediates PGE2 production in human monocytes activated with the vaccine adjuvant MDP.

Abstract

Vaccine adjuvants containing analogs of microbial products activate pattern recognition receptors (PRRs) on antigen-presenting cells, including monocytes and macrophages, which can cause prostaglandin E2 (PGE2) release and consequently undesired inflammatory responses and fever in vaccine recipients. Here, we studied the mechanism of PGE2 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 PGE2 followed by fever. In human monocytes, MDP alone did not induce PGE2 production. However, high amounts of PGE2 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 PGE2, IL-1β, and IL-6 in MDP + Tc CM-activated monocytes, whereas recombinant GPIbα protein increased PGE2 production by MDP-treated monocytes. In vivo, COX2 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 PGE2 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.

• Authors: Fengjie Liu, Yukinori Endo, Tatiana Romantseva, Wells W Wu, Adovi Akue, Rong-Fong Shen, Hana Golding, Marina Zaitseva
• Journal: Science signaling (Sci Signal) Vol. 12 Issue 602 (10 08 2019) ISSN: 1937-9145 [Electronic] United States
• PMID: 31594856 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Adjuvants, Immunologic
• Culture Media, Conditioned
• Interleukin-1beta
• Interleukin-6
• Macrophage-1 Antigen
• Nod2 Signaling Adaptor Protein
• Platelet Glycoprotein GPIb-IX Complex
• adhesion receptor
• Acetylmuramyl-Alanyl-Isoglutamine
• Dinoprostone
• Calcium

Topics

• Acetylmuramyl-Alanyl-Isoglutamine (pharmacology)
• Adjuvants, Immunologic (pharmacology)
• Animals
• Calcium (metabolism)
• Cells, Cultured
• Culture Media, Conditioned (pharmacology)
• Dinoprostone (metabolism)
• Female
• HEK293 Cells
• Humans
• Interleukin-1beta (genetics, metabolism)
• Interleukin-6 (genetics, metabolism)
• Macrophage-1 Antigen (genetics, metabolism)
• Mice, Knockout
• Monocytes (cytology, drug effects, metabolism)
• Nod2 Signaling Adaptor Protein (metabolism)
• Platelet Glycoprotein GPIb-IX Complex (genetics, metabolism)
• Rabbits
• Signal Transduction (drug effects)
• T-Lymphocytes (metabolism)
• THP-1 Cells