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C Bogdan

Publications and source records attributed to C Bogdan.

At least 19 recordsLinked to original sources
PubMed1992

Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10.

Transforming growth factor (TGF)-beta and interleukin (IL)-10 inhibited lipopolysaccharide (LPS)-induced macrophage production of the inflammatory cytokines tumor necrosis factor-alpha (TNF), IL-1 alpha, and IL-1 beta by contrasting post-transcriptional mechanisms. TGF-beta acted slowly and late, as it required 12-16 h to exert a suppressive effect, and inhibited TNF production even when added 6 h after LPS. TGF-beta affected neither the level of TNF mRNA, the release of preformed TNF nor the degradation of TNF. Thus, TGF-beta appeared to inhibit translation of TNF mRNA. IL-10 not only suppressed TNF release to a 25-fold greater extent than TGF-beta, but also inhibited release of IL-1. In contrast to TGF-beta, IL-10 acted on an early step in cytokine production, its effect being maximal 3 h after addition of LPS. Unlike TGF-beta, IL-10 markedly suppressed TNF, IL-1 alpha, and IL-1 beta mRNA levels. However, this was accomplished without suppressing transcription of the corresponding genes. Moreover, cycloheximide antagonized the IL-10-dependent reduction in cytokine mRNA levels. Thus, IL-10 may induce a ribonuclease active on cytokine transcripts or may induce a protein that enhances the susceptibility of TNF, IL-1 alpha, and IL-1 beta mRNAs to ribonucleolytic action. We conclude that IL-10 and TGF-beta induce different phenotypes of macrophage deactivation, and deactivate macrophages by different mechanisms: IL-10 promotes degradation of cytokine mRNA, while TGF-beta primarily suppresses translation.

Animals↗
PubMed1992

[Leishmaniasis with multiple cutaneous nodules].

Six weeks after a holiday trip to Yugoslavia, a previously well 48-year-old man developed a reddish-livid, firm nodule, 0.5 cm in diameter, on the proximal joint of the right thumb. A similar nodule appeared nearby, as well as over the left patella. Eleven additional nodules occurred over the next 4 months. His general health remained good and physical examination merely noted the liver edge palpable 3 cm below the costal margin. The histology of one of the nodules showed a tuberculoid, plasma-rich inflammatory reaction reminiscent of leishmaniasis or brucellosis. No organisms were seen. Immunohistochemistry of a frozen section demonstrated Leishmania-associated antigens, and the Western-blot test was characteristic for leishmaniasis. No systemic treatment was undertaken because of likely alcoholic toxic liver damage. On local treatment with paromomycin-containing ointment the cutaneous nodules healed without scar within 3 months.

Animals↗
PubMed1992

Acquired resistance and granuloma formation in experimental visceral leishmaniasis. Differential T cell and lymphokine roles in initial versus established immunity.

In naive BALB/c mice, acquisition of resistance to Leishmania donovani and formation of antileishmanial tissue granulomas are linked expressions that require both L3T4+ and Lyt 2+ cells as well as both IL-2 and IFN-gamma. To determine the mechanisms of established resistance to L. donovani, rechallenged immune BALB/c mice were treated with T cell- and lymphokine-depleting mAb or cyclosporin A. In the liver, resistance to rechallenge was inhibited by treatment with anti-Lyt 2 but not anti-L3T4 mAb. Resistance was also impaired by anti-IL-2 treatment but not by anti-IFN-gamma mAb. The hepatic granulomatous response to rechallenge, however, was not impaired by either anti-Lyt 2 or anti-IL-2 mAb nor by anti-L3T4 or anti-IFN-gamma treatment. In contrast, cyclosporin A suppressed granuloma formation but not antileishmanial activity. These results indicate a particularly important antileishmanial host defense role for Lyt 2+ cells and IL-2 in sensitized animals, and when compared to prior observations in L. donovani-infected naive mice, suggest that 1) discrete T cell- and lymphokine-dependent mechanisms are involved in initial acquisition of resistance vs established immunity, 2) more than one mechanism can mediate the development of tissue granulomas, and 3) granuloma formation by itself may not be required nor necessarily sufficient to confer antimicrobial activity.

Animals↗
PubMed1992

Taxol, a microtubule-stabilizing antineoplastic agent, induces expression of tumor necrosis factor alpha and interleukin-1 in macrophages.

Taxol, a naturally occurring diterpene with antitumor activity, induces tubulin polymerization to generate abnormally stable and nonfunctional microtubules. Previously, we showed that taxol has lipopolysaccharide (LPS)-like effects on macrophages. As LPS is a potent inducer of macrophage cytokine production, we investigated whether a similar effect is exerted by taxol. In a dose-dependent manner, LPS-free taxol induced release of biologically active tumor necrosis factor alpha (TNF) by inflammatory murine macrophages. Taxol-induced production of TNF was inhibitable by interleukin-10. By Northern blot, taxol (10 and 1 microM) induced TNF mRNA expression to an extent similar to LPS. Induction of TNF mRNA by 10 microM taxol was detectable at 45 min of stimulation, maximal at 90 min, and evident for at least 8 h. The same low concentration of taxol also induced interleukin 1 (IL-1) alpha and beta mRNA expression. We conclude that taxol triggers macrophages for TNF and IL-1 production. These LPS-like effects of taxol might contribute to its antitumor activity.

Alkaloids↗
PubMed1991

Macrophage deactivation by interleukin 10.

Recombinant mouse interleukin 10 (IL-10) was exceedingly potent at suppressing the ability of mouse peritoneal macrophages (m phi) to release tumor necrosis factor alpha (TNF-alpha). The IC50 of IL-10 for the suppression of TNF-alpha release induced by 0.5 microgram/ml lipopolysaccharide was 0.04 +/- 0.03 U/ml, with as little as 1 U/ml suppressing TNF-alpha production by a factor of 21.4 +/- 2.5. At 10 U/ml, IL-10 markedly suppressed m phi release of reactive oxygen intermediates (ROI) (IC50 3.7 +/- 1.8 U/ml), but only weakly inhibited m phi release of reactive nitrogen intermediates (RNI). Since TNF-alpha is a T cell growth and differentiation factor, whereas ROI and RNI are known to inhibit lymphocyte function, it is possible that m phi exposed to low concentrations of IL-10 suppress lymphocytes. m phi deactivated by higher concentrations of IL-10 might be permissive for the growth of microbial pathogens and tumor cells, as TNF-alpha, ROI, and RNI are major antimicrobial and tumoricidal products of m phi. IL-10's effects on m phi overlap with but are distinct from the effects of the two previously described cytokines that suppress the function of mouse m phi, transforming growth factor beta and macrophage deactivation factor. Based on results with neutralizing antibodies, all three m phi suppressor factors appear to act independently.

Animals↗
PubMed1991

Cytokine interactions in experimental cutaneous leishmaniasis. Interleukin 4 synergizes with interferon-gamma to activate murine macrophages for killing of Leishmania major amastigotes.

We investigated the effect of recombinant murine interleukin 4 (IL 4) in the absence or presence of recombinant murine interferon-gamma (IFN-gamma) on adherent bone-marrow macrophages (M phi), peritoneal exudate and resident peritoneal M phi from susceptible BALB/c M phi, which were pulse-infected with Leishmania major amastigotes (AM), IL 4 (5-100 U/ml) failed to activate any of these M phi populations for killing of intracellular AM. However, in the presence of low concentrations of IFN-gamma (10-20 U/ml), which alone caused only a slight or intermediate reduction of the number of intracellular parasites. IL 4 led to a dramatic increase of the parasite elimination by all M phi populations. In the case of resident peritoneal M phi, the synergism of IFN-gamma and IL 4 required the incubation of the M phi with both cytokines or with IFN-gamma alone for at least 10 h prior to infection; adding both cytokines after infection of the M phi did not cause a significant reduction of the intracellular parasite burden. The synergistic effect of IL 4 and IFN-gamma was completely abrogated in the presence of anti-IL 4 antibodies. Furthermore, there was no significant difference between M phi derived from either susceptible BALB/c or from resistant C57BL/6 mice. Evidence is presented that the synergistic action of IL 4 and IFN-gamma occurs via an L-arginine-dependent killing pathway. From these data we conclude that IL 4 provides a strong stimulus for the killing of intracellular L. major AM provided low concentrations of IFN-gamma are present. Also, IFN-gamma is apparently an important priming signal for the activation of resident M phi to eliminate intracellular AM.

Animals↗
PubMed1991

Cytokine interactions in experimental cutaneous leishmaniasis. II. Endogenous tumor necrosis factor-alpha production by macrophages is induced by the synergistic action of interferon (IFN)-gamma and interleukin (IL) 4 and accounts for the antiparasitic effect mediated by IFN-gamma and IL 4.

Tumor necrosis factor-alpha (TNF-alpha) strongly activates murine peritoneal macrophages (M phi) for killing of amastigotes from Leishmania major in the presence of low amounts of interferon-gamma (IFN-gamma). Recently, we found that IFN-gamma and interleukin 4 (IL 4) also synergistically enhance the antileishmanial potential of M phi. In this report, evidence is provided that the synergism of IFN-gamma and IL 4 is based on the ability of the lymphokines to induce the endogenous production of TNF-alpha. First, both IFN-gamma and IL 4 as single agents and in combination were potent inducers of TNF-alpha production by M phi infected with L. major amastigotes. Second, the synergistic effect of IFN-gamma and IL 4 on parasite killing by M phi strongly correlated with their synergistic effect on the release of TNF-alpha. Third, the IFN-gamma/IL 4-mediated parasite elimination was completely abrogated not only in the presence of antibodies to IFN-gamma and IL 4, but also with an antibody specific for TNF-alpha. Consistent with the conclusion that endogenously produced TNF-alpha accounts for the synergism of IL 4 with IFN-gamma is the finding that N omega-monomethyl-L-arginine, an inhibitor of the L-arginine-dependent generation of microbicidal nitrogen intermediates, totally blocked the M phi activation induced by IFN-gamma combined with IL 4 as well as by IFN-gamma combined with TNF-alpha. These results underline the complex interplay of cytokines derived from lymphocytes and M phi and the role of TNF-alpha as pivotal factor for the induction of antileishmanial effector functions.

Animals↗
PubMed1991

Cytokine interactions in experimental cutaneous leishmaniasis.

Destruction of intracellularly living Leishmania major amastigotes is achieved by activated macrophages. In this report, we have investigated the contribution of IL-4, TNF-alpha and IFN-gamma to the induction of antileishmanial macrophage activation. It was found that as single lymphokine only IFN-gamma led to amastigote elimination by peritoneal exudate macrophages. Neither IL-4 nor TNF-alpha or the combination of both cytokines led to antimicrobial activation. When the macrophages were incubated with concentrations of IFN-gamma that by themselves were insufficient for maximum cell activation, it was found that both IL-4 and TNF-alpha very effectively synergized with IFN-gamma for induction of antiparasitic activity. The activation which was achieved when IFN-gamma was combined with IL-4 could be blocked not only with antibodies to either of the lymphokines, but also with an antiserum specific for TNF-alpha, suggesting the involvement of endogenously generated TNF-alpha in this synergism. Any of the synergistic activities observed presumably lead to the activation of the L-arginine dependent pathway used by the cell for the production of nitrogen oxides as effector molecules for parasite killing since NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of this pathway, completely blocked the killing of intracellular parasites. We conclude that macrophage activation for antiparasitic activity is directed by a complex network of cytokine-interactions, in which IL-4 and TNF-alpha very effectively synergize positively with low levels of IFN-gamma.

Animals↗
PubMed1990

Tumor necrosis factor-alpha in combination with interferon-gamma, but not with interleukin 4 activates murine macrophages for elimination of Leishmania major amastigotes.

We have previously shown that during an infection with Leishmania major, susceptible BALB/c mice, as opposed to mice of a resistant strain (C57BL/6), are primed by lipopolysaccharide for the production of high levels of tumor necrosis factor-alpha (TNF-alpha) which is known to be a potent macrophage (M phi) stimulator in other parasitic diseases. In the present study we investigated whether TNF-alpha activates M phi for killing of L. major parasites. In the absence of interferon-gamma (IFN-gamma) or lipopolysaccharide, TNF-alpha (0.025-25,000 U/ml) failed to activate peritoneal exudate M phi from BALB/c mice for killing of L. major amastigotes. In the presence of suboptimal doses of IFN-gamma (5 or 10 U/ml), however, TNF-alpha mediated a rapid elimination of intracellular parasites, which was highly significant compared to IFN-gamma alone. The combination of TNF with interleukin 4, in contrast, was inactive in this respect and allowed survival of intracellular parasites. From these data we conclude that the presence of IFN-gamma is crucial for TNF-alpha-mediated killing of L. major parasites by M phi. Disease progression in susceptible mice therefore seems to be a consequence of a deficiency of IFN-gamma and a predominance of interleukin 4 rather than the result of an excess amount of TNF-alpha.

Animals↗
PubMed1990

Immunization of susceptible hosts with a soluble antigen fraction from Leishmania major leads to aggravation of murine leishmaniasis mediated by CD4+ T cells.

This study was performed in order to define Leishmania major antigens that function as disease-modulating immunogens in susceptible BALB/c mice. A soluble leishmanial antigen preparation (S-SLA) derived from highly infective stationary-phase L. major parasites was fractionated by preparative gel electrophoresis. In vitro, the low molecular mass fraction (less than 31 kDa) of S-SLA fraction D (FR D) was found to be a potent stimulator of L. major-specific Th1 and Th2 helper cell clones. In vivo, immunization with FR D induced a Th2-biased immune response in BALB/c mice as determined by the numbers of splenic CD4+ cells secreting interleukin 4 and interferon-gamma according to limiting dilution analyses. In addition, FR D caused significant disease exacerbation in parasite-infected susceptible mice as assessed by the local lesion development and the numbers of parasites in lymph nodes and spleen. This effect was observed after local subcutaneous application of FR D as well as after systemic immunization (intrasplenic or intraperitoneal). Transfer experiments revealed, that the disease-aggravating effect of FR D was mediated by CD4+ T cells. From these results it is concluded that leishmanial protein preparations exist that not only fail to induce protective anitparasitic immunity, but can mediate disease exacerbation, independently of the primary application site of the immunogen. The existence of such structures may serve the parasite as a means to evade the host's immune attack and may also have implications for the development of vaccines.

Animals↗
PubMed1990

Production of tumour necrosis factor during murine cutaneous leishmaniasis.

We have assessed the role of tumour necrosis factor-alpha (TNF) during cutaneous leishmaniasis and demonstrated that significant levels of TNF were released by spleen cells from infected mice after in vitro restimulation with Leishmania major promastigotes. Spleen cells from both genetically resistant and genetically susceptible mice were equally capable of producing TNF. After challenge with bacterial endotoxin, TNF activity could also be demonstrated in the serum of L. major-infected mice and the titres correlated with the course of cutaneous disease in susceptible and resistant mice. TNF did not exert a direct leishmanicidal effect in vitro. Furthermore, our study indicated that macrophages are the source of L. major-induced TNF activity and that its elicitation is dependent on the presence of T cells. These findings suggest that TNF acts in concert with other cytokines produced during L. major infection and that its role depends on the composition of T cell subsets and cytokines present.

Animals↗
PubMed1989

[Parasitic evasion mechanisms: Leishmania as an example].

Leishmania display a variety of mechanisms for effective evasion of the humoral and cellular immune responses of the host which are strongly associated with the expression of two major surface glycoconjugates, gp63 and lipophosphoglycan. The parasites are poor activators of the alternative complement pathway thus avoiding their own extracellular lysis. Complement bound on the surface of promastigotes promotes the uptake of leishmania by macrophages which function as "safe targets" as long as they are not activated by T lymphocytes. This is due to the fact that intracellular parasites are able to 1. decrease the oxidative burst; 2. scavenge toxic oxygen metabolites; 3. inhibit degradative lysosomal enzymes; 4. exploit the acidic milieu of lysosomes for their own metabolism. Finally, leishmania have been shown to evade the host's cellular immune response by down-regulating T cell-activating processes and by initiating the expansion of T cell subpopulations which promote their own survival.

Animals↗
PubMed1989

Cyclosporin A enhances elimination of intracellular L. major parasites by murine macrophages.

In this study we analyzed the influence of cyclosporin A (CyA) on the process of phagocytosis of L. major promastigotes and amastigotes by inflammatory peritoneal macrophages (MP) from BALB/c mice. Our data clearly demonstrate that CyA profoundly enhanced the degradation by peritoneal MP of both intracellular L. major promastigotes and amastigotes. This effect was T cell-independent and specifically associated with CyA, since the similarly structured cyclosporin F (CyF) was ineffective. CyA did not alter the replication and infectivity of extracellular parasites. From these results we conclude that the inhibition of intracellular parasite replication in the presence of CyA substantially contributes to the previously described suppressive effect of CyA on the development of L. major-induced lesions in BALB/c mice.

Animals↗
PubMed1987

Peculiarities of the endocrine time structure in noninsulin-dependent adult-onset (type II) diabetes mellitus.

Twenty noninsulin-dependent elderly diabetic patients, ten of whom were treated by oral hypoglycemic agents and ten of whom were regulated by diet alone, and 20 clinically healthy subjects matched for age, sex, height, and weight were examined with six blood and six urine samples at 4-hr intervals over a 24-hr span. Plasma ACTH, cortisol, aldosterone, and dehydroepiandrosterone-sulfate (DHEA-S) were determined by radioimmunoassay (RIA); epinephrine, norepinephrine, and dopamine in urine were determined by high-pressure liquid chromatography (HPLC); and magnesium in urine was determined colorimetrically on a DuPont ACA. There were a number of changes in some of these functions in type II diabetic patients with and without oral hypoglycemic agents that appear to be of interest. The circadian mean in plasma ACTH concentration in diabetic patients with and without oral hypoglycemic agents is significantly higher than in matched nondiabetic controls. The plasma aldosterone concentration is similar in type II diabetics treated by diet only and in matched controls but is statistically significantly elevated in patients on oral hypoglycemic agents. Correspondingly, the urinary excretion of sodium in type II diabetic patients on oral hypoglycemic agents is lower than in matched controls. The plasma cortisol concentration is unchanged in type II diabetic patients treated by diet alone but shows a slight increase in patients on oral hypoglycemic agents. The circadian means of plasma DHEA-S concentration is slightly higher in diabetic patients with and without oral hypoglycemic agents than in matched controls. This elevation, however, does not quite reach the 95% level of statistical significance. Urinary norepinephrine excretion in type II diabetic patients is similar to that in matched controls. The urinary epinephrine excretion in diabetics with and without oral hypoglycemic agents, however, was lower than in controls, and the urinary excretion of dopamine was higher in the diabetics. The urinary magnesium excretion in type II diabetic patients was lower than in matched controls.

Adrenal Cortex Hormones↗
PubMed1978

[Oral labor induction with PGE2-tablets].

Orally administered PGE2 in tablet form was used to induce labour in a prospective trial on 57 patients. The prostaglandin was given in separate-hourly-dosis of 0,5 to 1,5 mg. The success rate of this oral induction was 93%. Frequency of acidotic and/or clinically depressed newborns and the incidence of active delivery reflected the unselected population. A precipitant labour was noted in one patient, while 23% showed symptoms of gastrointestinal side effects which were seen to be dosage dependent.

Adult↗