A Potent Adjuvant Monophosphoryl Lipid A Triggers Various Immune Responses, but Not Secretion of IL-1β or Activation of Caspase-1

Abstract

Lipid A, the membrane anchor portion of LPS, is responsible for the endotoxin activity of LPS and induces many inflammatory responses in macrophages. Monophosphoryl lipid A (MPL), a lipid A derivative lacking a phosphate residue, induces potent immune responses with low toxicity. To elucidate the mechanism underlying the low toxicity of MPL, we examined the effects of MPL on the secretion of proinflammatory cytokines by mouse peritoneal macrophages, a murine macrophage-like cell line (RAW 264.7), and a human macrophage-like cell line (THP-1). MPL enhanced the secretion of TNF-α, but not that of IL-1β, whereas Escherichia coli-type lipid A (natural source-derived and chemically synthesized lipid A) enhanced the secretion of both cytokines. Although MPL enhanced the levels of IL-1β mRNA and IL-1β precursor protein to levels similar to those induced by lipid A, IL-1β precursor processing in MPL-treated cells was much lower than that in E. coli-type lipid A-treated ones. Moreover, MPL, unlike E. coli-type lipid A, failed to induce activation of caspase-1, which catalyzes IL-1β precursor processing. These results suggest that an immune response without activation of caspase-1 or secretion of IL-1β results in the low toxicity of this adjuvant.

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

“…Secretion of IL-1P induced by TLR4 agonists in the absence of exogenous ATP is codependent on MyD88 and TRIF Previous studies have reported weak IL-1f3 production by MLA [17,47]. We confirmed this finding in myeloid DCs using synthetic MLA to stimulate the cells in the absence of exogenous ATP, which showed weak production of IL-1f3 at all doses when compared to Lipid A.…”

“…TLR4 signaling alone is sufficient for production of significant levels of the inflammatory cytokine IL-1J3 [47], and although the levels of IL-1J3 produced by this mechanism are lower than with activation by experimental addition of A TP, they may be relevant in situations of chronic inflammation. For example, DAMPs recognized by TLR4 have been implicated in the pathogenesis of several inflammatory conditions including diabetes, arthritis, systemic lupus erythematosus, septic shock, stroke and myocardial infarct as well as Alzheimer and Crohn's disease, each of which has been linked to aberrant production of IL-1J3 and/or NLRP3 activation [67][68][69][70][71][72][73].…”

“…First, Okemoto et al. found that MPLA fails to stimulate secretion of the highly inflammatory cytokine IL-1 ~ to the same levels as LPS and traced this failure to defective activation of caspase-1, which is needed for proteolytic maturation of IL-1 ~ from its precursor prolL-1 ~ [47]. Subsequently, Mata-Haro et al…”

“…Two main hypotheses have been proposed for explaining MLA's reduced toxicity: i) that weak induction of IL-1J3 leads to decreased inflammation [47] and ii) that TRIF-biased activation of TLR4 results in weak induction of MyD88-dependent pro-inflammatory factors [17]. IL-1J3 is potent inflammatory cytokine that can potentiate MyD88 signaling through IL-1 RI.…”

Adjuvant formulations possess differing efficacy in the potentiation of antibody and cell mediated responses to a human malaria vaccine under selective immune genes knockout environment

“…On the other hand, adjuvants can have pleomorphic effects on a variety of cell types and this is much less appreciated. For example, monophosphoryl lipid As (MPLs) and its more toxic parent compound, LPS are thought to interact mainly via TLR4 ligation, but these compounds have differing effects on T cells and cytokine production [2][3][4][5][6][7][8][9][10]. The different cell types stimulated by MPL and LPS further add to the complexity of the effects of the adjuvants [2][3][4]9,11].…”