PubMed · 3574392
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1987-05-14. Progress in sleep.. https://doi.org/10.1056/nejm198705143162013
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Experiments were conducted to determine the effect of injection of lipopolysaccharide (LPS, from S. typhimurium) or muramyl dipeptide (MDP, N-acetylmuramyl-L-ala-isoglutamine) in Japanese quail. Doses of MDP between 0.3 and 10 mg/kg body wt. had no effect on body temperature. In contrast, doses of 1.0-22.5 mg LPS/kg body wt. caused significant increases in body temperature. None of the doses of LPS or MDP resulted in mortality. The febrile response to LPS was diminished following a second injection 48 h after the first, and was absent following a third injection. Plasma zinc, an indicator of the acute phase response, was significantly reduced by either LPS or MDP after the first injection (P<0.001), but not after the second or third injection. Splenic interleukin 1-beta (IL-1beta) mRNA expression was increased after the first and last injection of LPS (P<0.001), but only after the first injection of MDP (P<0.005). Hepatic IL-1beta mRNA expression was increased after the first, but not the third injection of LPS (P<0.001), while MDP had no effect. These data indicate that Japanese quail are less sensitive to MDP than LPS, and that quail demonstrate tolerance to LPS following repeated injections.
The novel applications of a muramyl dipeptide analogue, romurtide, were investigated. When mice were intravenously injected with 10-1000 micrograms/mouse of romurtide as a primer and 3 KE/mouse of OK-432 as a trigger, systemic tumor necrosis factor-alpha (TNF-alpha) activity was increased. Similar effects were also detected by oral administration of romurtide at 1000 to 10,000 micrograms/mouse. These effects reached maximum at 3 h (intravenous injection, i.v.) or 6 h (oral administration, p.o.) after administration and were sustained for 48 h. When romurtide was administered to MM46 tumor-bearing mice orally, the significant augmentation of TNF-alpha production could be detected in the solid tumor and the liver. When romurtide was intravenously injected to the tumor bearer, the TNF-alpha production was significantly augmented in the spleen. These findings suggest that romurtide can augment the host defense system by both the parenteral and oral route, and indicate the possibility of a new type of anti-tumor therapy to induce TNF-alpha in the tumor region.
Earlier studies showed that Micrococcus luteus cells and cell walls induced anaphylactoid reactions leading to death, in some instances within 1 h, in C3H/HeN mice primed with muramyl dipeptide (MDP). They also induced serum cytokines in the surviving mice. The present study investigated the structural components responsible for these activities. Teichuronic acids, a component of M. luteus cell walls, induced tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in MDP-primed C3H/HeN mice. Peptidoglycans had little effect on the cytokine-inducing activities. Reducing teichuronic acids, i.e., teichuronic acids whose carboxyl groups had been reduced, lost their cytokine-inducing activities. Neither peptidoglycans nor teichuronic acids induced anaphylactoid reactions in the MDP-primed mice. Purified teichuronic acids also induced TNF-alpha and IL-6 production in C3H/HeN murine peritoneal macrophages and human whole-blood cells in the culture, but reduced teichuronic acids did not. The purified teichuronic acids induced no TNF-alpha and only low levels of IL-6 in MDP-primed C3H/HeJ mice, and neither cytokine in peritoneal macrophage cultures from C3H/HeJ mice with a single point of mutation in Toll-like receptor 4 (TLR4) gene. These findings suggest that induction of cytokines by teichuronic acids is mainly TLR4-dependent.