Stimulation of nonspecific resistance to infection induced by 6-O-acyl muramyl dipeptide analogs in mice

Beige mutant (bg/bg) mice with Chediak‐Higashi syndrome (CHS) were much more sensitive to virulent Salmonella enteritidis No. 11 strain than parental C57 BL/6 (+/+) or heterozygous (bg/ +) mice, and they had weaker bactericidal activity against the organisms. Muramyl dipeptide (MDP) and Nα‐(N‐acetyl‐muramyl‐L‐alanyl‐D‐isoglutamyl)‐Nε‐stearoyl‐L‐lysine [MDP‐Lys(L18)], a synthetic derivative of MDP, failed to confer any protection against the infection, but the MDPs showed some ability to stimulate the bactericidal activity in the peritoneal cavities and spleens of these mice. The bactericidal effect of MDP‐Lys(L18) was dose‐dependent, and the greatest effect was seen when it had been injected 24 hr before the infection. Multiple injections of MDP were much more beneficial than a single injection. Previous injection of N2, O2′‐dibutyryl guanosine 3′: 5′‐cyclic monophosphate (DB‐cGMP) improved the impaired bactericidal capacity in beige mice, but the simultaneous injection of N6, O2′‐dibutyryl adenosine 3′: 5′‐cyclic monophosphate (DB‐cAMP) with DB‐cGMP abolished the effect of DB‐cGMP. The augmentation of bactericidal capacity by MDP‐Lys(L18) was not affected by the injection of either DB‐cGMP or DB‐cAMP, suggesting that the effect of the MDPs was not related directly to cyclic nucleotide regulation in beige mice.

Section: Discussionsupporting

confidence: 93%

Effect of Muramyl Dipeptide Analog on Salmonella enteritidis Infection in Beige Mice with Chediak‐Higashi Syndrome

Onozuka¹,

Saito‐Taki²,

Nakano³

1984

“…In preliminary experiments, daily administration of 0.3 mg/kg LSN B for five days resulted in a sixfold increase in peripheral neutrophils, but no There are several low molecular weight compounds, for example N-muramyl-L-alanyl-D-isoglutamine (MDP), its analogues, D-lactyl-L-alanyl-D-glutamyl-(L)-meso-diaminopi menyl-(L)-glycine ( FK-156) and isohematinic acid, which enhance the function of neutrophils and thereby augment host resistance to bacterial infection (4,8,13,18). When the activities of some of these compounds are compared with that of LSN B, in our assay system (18), the effects of LSN B were stronger than those of MDP and isohematinic acid, and comparable with those of human recombinant G-CSF (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Augmentation of Host Resistance against Bacterial Infection by Treatment with Leustroducsin B, a New CSF Inducer

Kohama

Katayama²,

Inukai³

et al. 1994

We tested the in vivo activity of leustroducsin B (LSN B), a new colony-stimulating factor (CSF) inducer isolated from the culture broth of Streptomyces platensis, with mice infected with Escherichia coli. Treatment with LSN B augmented the host resistance to lethal infection of E. coli at doses between 0.1 mg/kg and 1 mg/kg. Serum interleukin-6 (IL-6) levels were found to increase after this treatment, and superoxide anion generation of neutrophils was enhanced in vivo, suggesting that LSN B augmented the host resistance at least in part by inducing IL-6, which subsequently enhanced the bactericidal activity of the neutrophils.

“…MDP produces only a weak increase in [3H]thymidine uptake by murine splenocytes compared to LPS (6,29,30), but has no effect on thymocytes (31). Synthetic MDP-Lys (L18) is one of the most efficacious analogs of MDP (14,24). None of these mitogens showed any effects on the proliferation of cultures reconstitutedfrom human peripheral blood T cell and B cell populations.…”

Section: Discussionmentioning

confidence: 99%

Role of Interleukin 2 on Enhancement of Concanavalin A‐Induced Human Peripheral Blood Lymphocyte Proliferation by Murine B Cell Mitogens

Nitta

Konno-Ejiri

Okumura

et al. 1985

Murine B cell mitogens such as bacterial lipopolysaccharide (LPS), butanol-extracted water soluble adjuvant (Bu-WSA), dextran sulfate (DS), synthetic muramyl dipeptide (MDP), and its analog MDP-Lys (L18) do not show any mitogenic ability in vitro on human peripheral blood lymphocytes or mixed cell populations of purified T and B cells obtained from the lymphocytes in an ordinary culture system. However, these mitogens are capable of enhancing the mitogenic effect of concanavalin A (Con A) in the cultures.In the presence of one of these mitogens, the activity of interleukin 2 (IL 2), but not interleukin 1, in the supernatants obtained from cultures containing Con Astimulated T cell and B cell populations was higher than that of control cultures. The role of the newly produced IL 2 in the synergistic effect of the mitogens in human lymphocyte cell cultures was discussed.Concanavalin A (Con A) is one of the potent mitogens for T lymphocytes (8), but the proliferative response of T lymphocytes requires the presence of Ia-positive accessory cells such as macrophages or B lymphocytes (2, 27). Human peripheral T lymphocyte proliferation by Con A is augmented further in the presence of bacterial lipopolysaccharide (LPS) (13, 26) or butanol-extracted, water soluble adjuvant (Bu-WSA) obtained from Bacterionema matruchotii, gram positive oral bacteria (21). Although LPS (10) and Bu-WSA (19) are B cell mitogens in mice, these B cell mitogens do not appear to activate human peripheral B lymphocytes under ordinary experimental conditions (25, 26), much less peripheral T lymphocytes.The triggering of human lymphocytes and the mechanism(s) of activation are subjects of intense interest and investigation. Affects of so-called B cell mitogens on Con A-induced T cell proliferation display a complexity of mitogenic responses. The object of the present study was to investigate whether synergistic effects could be seen on Con A-induced human peripheral blood lymphocyte proliferation in vitro when other kinds of B cell mitogens were used instead of LPS or Bu-WSA and 44 1