title: Muramyldipeptide augments the actions of lipopolysaccharide in mice by stimulating macrophages to produce pro-IL-1β and by down-regulation of the suppressor of cytokine signaling 1 (SOCS1).
abstract: Muramyldipeptide (MDP), the minimum essential structure responsible for the immuno-adjuvant activity of peptidoglycan, is recognized by intracellular nuclear-binding oligomerization domain 2 (NOD2). Muramyldipeptide enhances the activities of lipopolysaccharide (LPS), but the mechanism underlying this effect is unclear. Here, we obtained evidence that intravenously injected MDP augments LPS-induced hypothermia in wild-type mice, but not in mice deficient in interleukin (IL)-1α/β and/or tumor-necrosis factor (TNF)-α. Muramyldipeptide also: (i) increased pro-IL-1β in tissues, but did not increase IL-1β in serum (since caspase-1 was not activated by MDP); (ii) downregulated the expression of suppressor of cytokine signaling 1 (SOCS1; a negative-feedback regulator of LPS-induced signaling); and (iii) augmented the LPS-induced production of TNF-α, IL-12 p40, and interferon (IFN)-γ. Moreover, by performing in vivo and in vitro experiments, we obtained evidence that macrophages were involved in these effects of MDP. These results suggest that two different mechanisms may underlie the augmenting effect of MDP: namely, stimulation of pro-IL-1β production by, and down-regulation of SOCS1 in, macrophages. We consider that this work may help to elucidate the pathogenesis of mixed bacterial infections, including septic shock and multiple organ dysfunction syndrome (MODS).
authors.affiliation: Divisions of Periodontology and Endodontology, Graduate School of Dentistry, Tohoku University, Sendai, Japan. shikama-thk@umin.ac.jp
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Shikama
authors.forename: Toshinobu
authors.initials: T
authors.lastname: Kuroishi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nagai
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Shimauchi
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Takada
authors.forename: Shunji
authors.initials: S
authors.lastname: Sugawara
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Endo
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000008:administration & dosage / Q000494:pharmacology*; D000825:Animal Structures / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D020170:Caspase 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D004002:Clodronic Acid / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D007371:Interferon-gamma / Q000097:blood; D053762:Interleukin-12 Subunit p40 / Q000097:blood / Q000378:metabolism; D053582:Interleukin-1alpha / Q000235:genetics; D053583:Interleukin-1beta / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D012772:Shock, Septic / Q000139:chemically induced / Q000503:physiopathology; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics / Q000378:metabolism
chemical_list: D053762:Interleukin-12 Subunit p40; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D011498:Protein Precursors; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; C482199:lipopolysaccharide, E coli O55-B5; D004002:Clodronic Acid; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D007371:Interferon-gamma; D020170:Caspase 1