M. Guenounou

Differential regulation of TNFα, IL-1β, IL-6, IL-8, TNFβ, and IL-10 by pentoxifylline

Abstract Pentoxifylline (PTX) is a methylxanthine drug known to inhibit the production of tumor necrosis factor-alpha (TNFα), which plays a key role in inflammation. Recent studies also revealed that other cytokines may be inhibited by PTX. We investigated PTX effects on production and mRNA expression of TNFα, IL-1β, IL-6, IL-8, TNFβ and IL-10. Cytokine release was studied in 1/10 diluted whole blood culture (WB) and in peripheral blood mononuclear cell (PBMC) culture. Cytokine production was triggered in both culture systems by endotoxin (LPS) or by phorbol ester (PMA) plus phytohemagglutinin (PHA). Our results showed that expression and production of TNFα and TNFβ were inhibited by PTX in a dose-dependent manner. Moreover, we observed that depending on the way of activating cells, PTX induced an up- or a down-regulation (in PMA+PHA or LPS stimulated cells, respectively) for IL-1 and IL-6 release. We also noted that the effects of PTX on IL-6, IL-8 and IL-10 production were different in WB and in PBMC culture. In conclusion PTX acts on cytokine in a complex manner depending on cellular environment and on the method of activation.

Induction of interleukin 1 secretion by murine macrophages and human monocytes after stimulation by RU 41740, a bacterial immunomodulator

RU 41740, a glycoprotein extract from K. pneumoniae K2O1 strain, is an immunomodulating compound which has been shown to reduce infectious episodes in patients prone to recurrent infections. Data from preliminary experiments suggest that RU 41740 may affect several target cells, including T cells, B cells or macrophages. In the present report we show that RU 41740 can trigger mouse macrophages and human adherent mononuclear cells to produce interleukin 1 activity. Indeed, supernatants from mouse peritoneal adherent cells and human monocytes incubated in presence of RU 41740, can stimulate blastogenesis in thymocytes from C3H/HeJ mice. The data suggest that the immunomodulating effect of RU 41740 could be related to its ability to induce interleukin 1 production.

Immunological activities of RU-41740, a glycoproteic extract from Klebsiella pneumoniae. I: Activation of murine B cells and induction of interleukin-1 production by macrophages

RU-41740, a glycoprotein extract from Klebsiella pneumoniae K2O1 strain, is an immunomodulating compound which has been shown to reduce infectious episodes in immunodeficient patients. Data from preliminary experimental designs suggested that RU-41740 could affect several target cells, such as T cells, B cells and macrophages. In the present report, we show that RU-41740 is a selective B-lymphocyte activator. It induces blast transformation in Nude mouse spleen cell cultures and in B-cell-enriched fractions obtained from normal mice. It does not activate T lymphocytes to proliferate. Activation of mouse B lymphocytes by RU-41740 is not affected by removal of adherent cells. RU-41740 also activates immunoglobulin secretion by murine B lymphocytes. Incubating spleen cells from C3H/HeJ mice with RU-41740 results in cell proliferation and activation of antibody-forming cells. This suggests that B-cell activation is not due to LPS contamination. Other experiments show that RU-41740 can also trigger mouse macrophages to produce interleukin-1 activity. Indeed, supernatants from peritoneal adherent cells incubated in the presence of RU-41740 can stimulate blastogenesis in thymocytes from C3H/HeJ mice. Thus, B-cell activation and IL-1 production by macrophages could constitute two additive mechanisms involved in immunomodulation induced by RU-41740.

RU-41740 (K. Pneumoniae Glycoprotein) enhances resistance to experimental candidiasis and stimulates phagocytic functions

Summary RU-41740, a purified glycoprotein extract from Klebsiella pneumoniae , (which is an efficient non-specific immune activator in a broad spectrum of in vitro and in vivo reactions) was administered either orally or parenterally in the mouse. It enhanced the resistance of mice to candidiasis, both in terms of survival rate and a decrease in viable yeast cell recovery in kidneys. The drug administered at 0.1 mg or 1 mg/kg augmented 4-fold the mean survival time (MST) of animals infected with 1 to 2 x 10 6 Candida albicans , both by the intraperitoneal and the intravenous route. The effect of the orally administered drug was less striking but nonetheless present. At 10 mg/kg, the MST of infected animals increased about 2-fold. In vitro , in the presence or absence of zymozan, the drug at 10 or 100 μ/ml was able to stimulate the phagocytic process of elicited mouse peritoneal cells (65 % polymorphonuclear cells, 35 076 macrophages) and human peripheral blood cells (95 % polymorphonuclear cells, 5 % monocytes) in terms of activated oxygen species production. The involvement of polymorphonuclear cells in the mechanisms of natural resistance to C. albicans infection led us to discuss the role of these cells as targets for the drug.

RU 41740 (K. pneumoniae glycoprotein) enhances resistance to experimental candidiasis and stimulates phagocytic functions

RU-41740, a purified glycoprotein extract from Klebsiella pneumoniae, (which is an efficient non-specific immune activator in a broad spectrum of in vitro and in vivo reactions) was administered either orally or parenterally in the mouse. It enhanced the resistance of mice to candidiasis, both in terms of survival rate and a decrease in viable yeast cell recovery in kidneys. The drug administered at 0.1 mg or 1 mg/kg augmented 4-fold the mean survival time (MST) of animals infected with 1 to 2 X 10(6) Candida albicans, both by the intraperitoneal and the intravenous route. The effect of the orally administered drug was less striking but nonetheless present. At 10 mg/kg, the MST of infected animals increased about 2-fold. In vitro, in the presence or absence of zymosan, the drug at 10 or 100 micrograms/ml was able to stimulate the phagocytic process of elicited mouse peritoneal cells (65% polymorphonuclear cells, 35% macrophages) and human peripheral blood cells (95% polymorphonuclear cells, 5% monocytes) in terms of activated oxygen species production. The involvement of polymorphonuclear cells in the mechanisms of natural resistance to C. albicans infection led us to discuss the role of these cells as targets for the drug.