Immune Complex/Ig Negatively Regulate TLR4-Triggered Inflammatory Response in Macrophages through FcγRIIb-Dependent PGE2 Production

Abstract

Excessive activation of TLR may induce endotoxin shock and inflammatory diseases, so the negative regulation of TLR-triggered inflammatory response attracts much attention. Nonpathogenic immune complex (IC) and Ig (IC/Ig) have been shown to play important roles in the regulation of immune responses and to be therapeutic in some kinds of autoimmune diseases. However, the role of IC/Ig in the regulation of TLR-triggered inflammatory responses and the underlying mechanisms remain to be fully understood. In this study we demonstrate that IC/Ig can significantly inhibit LPS-induced secretion of TNF-␣ and IL-6 from macrophages by preferentially inducing PGE 2 . Pretreatment of mice with IC can protect wild-type mice, but not Fc␥RIIb ؊/؊

Calcium/calmodulin‐dependent protein kinase II regulates cyclooxygenase‐2 expression and prostaglandin E2 production by activating cAMP‐response element‐binding protein in rat peritoneal macrophages

“…Usually, the phosphorylation of cPLA 2 at its serine residues is mediated by protein kinases, including mitogen-activated protein kinase (MAPK) and MAPK-interacting kinase. The binding of Ca 2+ to the N-terminal C 2 domain of cPLA 2 induces the translocation of cPLA 2 from the cytosol to the plasma membrane, where it catalyses the conversion of AA into PGE 2 .…”

“…Usually, the phosphorylation of cPLA 2 at its serine residues is mediated by protein kinases, including mitogen-activated protein kinase (MAPK) and MAPK-interacting kinase. The binding of Ca 2+ to the N-terminal C 2 domain of cPLA 2 induces the translocation of cPLA 2 from the cytosol to the plasma membrane, where it catalyses the conversion of AA into PGE 2 . [15][16][17] On the other hand, COX-2 expression is associated with the activation of transcription factors, such as nuclear factor-jB, nuclear factor of activated T-cell, cAMPresponse element binding protein (CREB) and CCAAT/ enhancer binding protein b (c/EBPb).…”

“…In response to stimulants, macrophages produce numerous pro-inflammatory cytokines and secondary mediators, which are pivotal for the innate and adaptive immune responses. 1,2 Uncontrolled expression of the substances can initiate septic shock syndrome, which is characterized as fever, hypotension, disseminated intravascular coagulation and multiple organ failure. 3,4 Among these factors, prostaglandin E 2 (PGE 2 ) is an essential mediator that contributes to vasodilatation, pain and fever.…”

“…7,8 In macrophages, PGE 2 production is tightly controlled by arachidonic acid (AA) release and cyclooxygenase-2 (COX-2) expression. 9,10 For AA release, the activation of calcium-dependent cytosolic phospholipase A2 (cPLA 2 ) plays an essential role, which catalyses the hydrolysis of membrane phospholipid into AA. 11,12 In turn, COX-2 converts AA into PGE 2 .…”

“…13,14 To achieve its full activation, cPLA 2 needs to binds to Ca 2+ and be phosphorylated at the serine residues. Usually, the phosphorylation of cPLA 2 at its serine residues is mediated by protein kinases, including mitogen-activated protein kinase (MAPK) and MAPK-interacting kinase.…”