Selective Activation of the p38 MAPK Pathway by Synthetic Monophosphoryl Lipid A

Abstract

TLR4 stimulation by lipopolysaccharide can cause both MAL/MyD88-and TRAM/TRIF (Toll IL-1 receptor domaincontaining adaptor-inducing IFN␤)-dependent signaling events. Monophosphoryl lipid A (MPLA), a low toxicity derivative of endotoxic lipopolysaccharide, enhances antibody responses, T cell expansion, and recall responses against antigens without causing excessive inflammatory side effects. Previously, we proposed that TRIF-biased activation of TLR4 by MPLA is responsible for its reduced toxicity while retaining potent adjuvant effects. However, some TRIF-associated genes, such as MCP-1, are only weakly expressed, and some MyD88-associated inflammatory and anti-inflammatory cytokines, such as tumor necrosis factor ␣ and interleukin-10, are strongly activated after MPLA stimulation despite weak NF-B but strong IRF3 activation. We now report that synthetic derivatives of MPLA retained TRIF bias as compared with synthetic diphosphoryl lipid A, indicating a change in a single phosphoryl group is sufficient for TRIF-biased TLR4 stimulation. We extend our previous observations by showing that sMLA induces strong p38 MAPK but weak JNK activation, resulting in high IP-10 (interferon-inducible protein 10), tumor necrosis factor ␣, and interleukin-10 but low MCP-1 transcript levels. Results of this study identify a novel biochemical mechanism for regulation of sMLA-induced gene expression.

Carbohydrate-Based Adjuvants for Vaccine Production

“…По сравнению с ЛПС МФЛ обладает низкой токсичностью, но сохраняет иммуностимулирующую активность [63]. Снижение реактогенности по сравнению с ЛПС объясняется тем, что передача сигнала МФЛ через ре-цепторы TLR4 осуществляется преимущественно посредством адаптора TRIF вместо адаптора MYD88 [64]. МФЛ используется в различных патентованных адъювантных составах, в том чис-ле адъювантах AS02 и AS04 (компании GSK), где МФЛ приме-няется в комбинации с QS21 и эмульсией типа «масло-в-воде», либо с гидроксидом алюминия соответственно.…”

Reconciliation of IL-1ß loss with TRIF-biased TLR4 signaling by monophosphate lipid A.

“…In the current study, IL-1J3 was not detectable in culture supernatants within 1 h of treatment with Lipid A or MLA, which is the time frame when TRIF-biased signaling by MLA was evident in the previous studies [17,48].…”

“…The receptor for IL-1J3, IL-1RI, requires MyD88 as a signaling adaptor and it is therefore formally possible that the greater amounts of IL-1 J3 released by Lipid A-stimulated cells generated the higher levels of MyD88-associated outcomes, relative to TRIF-biased MLA, that we previously observed when comparing Lipid A and MLA [17,48]. In the current study, IL-1J3 was not detectable in culture supernatants within 1 h of treatment with Lipid A or MLA, which is the time frame when TRIF-biased signaling by MLA was evident in the previous studies [17,48].…”

“…reported that MPLA signals through TLR4 in a TRIF-biased manner characterized by impaired stimulation of MyD88-dependent signaling events, relative to Lipid A or LPS [17,48]. In this second model, weak MyD88 signaling is proposed to account for reductions in a broad range of inflammatory activities with little impairment of TRIF-dependent promotion of adaptive immune responses.…”

“…We previously demonstrated that MLA, used clinically in vaccine preparations as MPL adjuvant®, is a TRIF-biased agonist of TLR4 [17,48], and argued that this TRIF-bias likely explains its low toxicity profile. Others have concluded that MLA's failure to induce IL-1~ is responsible for decreased toxicity [47].…”