A potent adjuvant monophosphoryl lipid A triggers various immune responses, but not secretion of IL-1beta or activation of caspase-1.
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-alpha, but not that of IL-1beta, 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-1beta mRNA and IL-1beta precursor protein to levels similar to those induced by lipid A, IL-1beta 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-1beta precursor processing. These results suggest that an immune response without activation of caspase-1 or secretion of IL-1beta results in the low toxicity of this adjuvant.
Okemoto
Kazuo
K
Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan.
Kawasaki
Kiyoshi
K
Hanada
Kentaro
K
Miura
Masami
M
Nishijima
Masahiro
M
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D020170:Caspase 1 / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D053471:Caspases, Initiator; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis*; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D011499:Protein Processing, Post-Translational / Q000187:drug effects
D000276:Adjuvants, Immunologic; D007375:Interleukin-1; D008050:Lipid A; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1; C048436:monophosphoryl lipid A