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Malaria toxins: TNF-mediated phenomena
Abstract
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... It is now apparent that the components of malaria toxin preparations which induce hypoglycaemia differ from those which induce the production of TNF [17], that TNF-inducing molecules differ from those which mimic or synergize with insulin [35], and that parasitized erythrocytes contain molecules which resemble mammalian insulin-mimetic inositolphosphoglycans [36]. We also have evidence from experiments in vitro with pancreatic islets isolated from rats that parasite-derived molecules can stimulate pancreatic -cells directly to secrete insulin (Elased, unpublished work). ...
Hypoglycaemia in falciparum malaria is associated with a poor prognosis and is correlated with mortality. High levels of serum TNF are also correlated with disease severity and mortality, and it has been suggested that TNF may cause the hypoglycaemia. However hypoglycaemia in mice infected with Plasmodium chabaudi or the lethal strain of P. yoelii YM is related to hyperinsulinaemia. Its development was not prevented by treatments which diminished TNF activity or production without affecting levels of plasma insulin. Conversely, it was inhibited by diazoxide, which inhibited insulin secretion but did not affect TNF production. Furthermore, in mice exhibiting neurological symptoms during infection with P. berghei, blood glucose concentrations were significantly raised when TNF levels were high, and TNF levels in the spleen were highest of all in non-lethal P. yoelii infections in which hypoglycaemia does not occur. Administration of human rTNF to normal animals caused an increase rather than a drop in blood glucose levels. Mice transgenic for human TNF did not develop hypoglycaemia when infected with P. yoelii YM, but showed signs of insulin resistance. In line with current views on the role of TNF in obesity and the control of glucose homeostasis, we conclude that the hypoglycaemia of malaria is not caused by increased levels of TNF, which may in fact be beneficial, but is secondary to a hyperinsulinaemia that is probably stimulated directly by products of the parasite.
... 20 Experiments with glucose uptake into adipocytes suggested similar but probably not identical molecules with several effects on glucose metabolism; the components of ''malaria toxin'' preparations that induced TNF were different from those that induced hypoglycemia and synergized with insulin. 21,22 We propose that when fully characterized, the latter might form the basis for treatment of both type 1 and type 2 diabetes. Indeed, one case has been reported in which P falciparum infection induced hypoglycemia not related to quinine therapy in a patient with NIDDM. ...
C57BL/KsJ-db/db and C57BL/KsJ-ob/ob mice are good models for studies on human obesity and type 2 diabetes. We have previously shown that infection with blood-stage malaria or injection of extracts from malaria-parasitized red blood cells induces hypoglycemia in normal mice and normalizes hyperglycemia in mice made moderately diabetic by streptozotocin. In the present study, we show that a single intravenous (IV) injection of Formalin-fixed Plasmodium yoelii YM (FFYM) preparation decreases blood glucose in db/db mice from an initial value of 19 mmol/L to a normal value of 7 mmol/L (P < .0001) for at least 24 hours and reduces food intake. Plasma insulin concentrations in db/db mice were not altered. FFYM was also active in normal and ob/ob mice, an effect associated with an increase in plasma insulin. Although the rate of weight gain in lean ob/+ and lean db/+ was not altered by this treatment, there was a significant reduction in weight gain in db/db and ob/ob mice (P < .001). We suggest that malaria-derived molecules, when fully characterized, may provide structural information for the development of new agents for the management of type 2 diabetes.
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Iron chelating agents, which permeate through erythrocytic and parasite membranes, are effective against Plasmodium falciparum in vitro. However, the protective effect in humans is transient. We examined the antiplasmodial capacity of several iron chelators in vitro and in vivo. The chelators 3/3hb/2m and 3/2hb/b (together, MoB) were more effective against P. falciparum in vitro than desferrioxamine (DFO) and Salicylaldehyde isonicotinoyl hydrazone (SIH) (together, DoS). Despite similar pharmacokinetics of all iron chelators, mice infected with Plasmodium vinckei and treated with MoB succumbed to malaria, whereas DoS-treated mice survived. However, even in the surviving mice, peak parasitemias were above 30%. These results indicate that the direct effects of the drugs on the parasites were not responsible alone for the complete recovery of the mice. We suggest that the recovery is related to differential effects of the drugs on various immune functions. We concentrated on the effect of the iron chelators on B cell and T cell proliferation and on allogeneic stimulation (MLR), interleukin-10 (IL-10), gamma-interferon (gamma-IFN), tumor necrosis factor-alpha (TNF-alpha), and radical production. All the iron chelators examined inhibited the in vitro proliferation of B cells and T cells, and MLR. This may explain why iron chelators are only slightly efficient in treating human malaria. However, the inhibitory effects of MoB on B cell and T cell proliferation and on MLR were more pronounced than those of DoS. In addition, the release of free radicals by effector cells was inhibited to a greater extent by MoB than by DoS. These results may explain why MoB, which was more efficient in vitro, was not effective in vivo. The DoS effects on the in vitro secretion of cytokines correlate with their in vivo effect; there was a decrease of IL-10 and a parallel increase in gamma-IFN and TNF-alpha production by human mononuclear cells. MoB, which could not rescue the animals from malaria, did not affect IL-10 and TNF-alpha, but reduced gamma-IFN levels. Identical results were obtained when using monocytes instead of mononuclear cells (except for gamma-IFN, which is not produced by monocytes). Our results indicate that an iron chelator, or any antiparasitic drug that kills the parasites in vitro, should also be selected for further evaluation on the basis of its reaction with immune components; it should not interfere with crucial protective immunological processes, but it may still alleviate parasitemia by positive immune modulation.
Tumor necrosis factor-alpha (TNF) has recently been shown to induce insulin resistance. We have examined the possible effect of TNF on the early events in insulin transmembrane signaling. Incubation of the insulin-sensitive rat hepatoma Fao cells with 5 nM TNF for 1 h led to a 65% decrease in insulin-induced tyrosine phosphorylation of both the insulin receptor beta-subunit and IPS-1, its major cytosolic substrate. TNF-induced impairment of tyrosine phosphorylation was maximal at 0.5 nM and was not accompanied by any reduction in insulin binding. Sixteen hours of TNF incubation led to further impairment in insulin-induced tyrosine phosphorylation of these proteins. Our findings suggest that TNF may exert its anti-insulin effect by interrupting the early insulin-stimulated tyrosine phosphorylation events, which are crucial to insulin transmembrane signature.
Epidermal growth factor (EGF) stimulates lipogenesis by 3-4-fold in isolated adipocytes, with a half-maximal effect at 10 nM-EGF. In the same batches of cells insulin stimulated lipogenesis by 15-fold. Freezing and prolonged homogenization of adipocytes results in release of large quantities of pyruvate carboxylase from broken mitochondria, and sufficient pyruvate can be carried through into assays for this enzyme to cause significant interference with assays of acetyl-CoA carboxylase in crude adipocyte extracts. This may account for the high amount of citrate-independent acetyl-CoA carboxylase activity reported to be present in adipocyte extracts in some previous publications. This problem may be eliminated by homogenizing very briefly without freezing. By using the modified homogenization procedure, EGF treatment of adipocytes was shown to produce an effect on acetyl-CoA carboxylase activity almost identical with that of insulin. Both messengers increase Vmax. without significant effect on the Ka for the allosteric activator, citrate.
Severe hypoglycemia developed during nonlethal Plasmodium chabaudi and lethal P. yoelii blood stage malaria infection in mice, always in association with hyperinsulinemia. Supernatants of lethal P. yoelii incubated overnight induced hypoglycemia and hyperinsulinemia in normal mice. In murine malaria, hypoglycemia may be largely secondary to increased insulin secretion.
Hypoglycaemia is a major complication of severe malaria [(1990) Trans. Roy. Soc. Trop. Med. 84 (suppl. 2) 1-65], especially cerebral malaria, in which it is associated with increased mortality [(1990) Lancet 336, 1039-1043; (1989) Quart. J. Med. (New series) 71, 441-459]; however, the mechanisms responsible have not been fully explained. Preparations containing toxic malaria antigens (TMA) released by blood stage Plasmodium yoelii malaria parasites have been shown to induce hypoglycaemia in mice lasting at least 8 h [(1992) Clin. Exp. Immunol. (in press)]. Here we report that TMAs can act synergistically with insulin in both stimulating lipogenesis and inhibiting lipolysis in rat adipocytes in vitro, and, furthermore, that they act synergistically with insulin in the induction of hypoglycaemia in vivo.
Guidelines for submitting commentsPolicy: Comments that contribute to the discussion of the article will be posted within approximately three business days. We do not accept anonymous comments. Please include your email address; the address will not be displayed in the posted comment. Cell Press Editors will screen the comments to ensure that they are relevant and appropriate but comments will not be edited. The ultimate decision on publication of an online comment is at the Editors' discretion. Formatting: Please include a title for the comment and your affiliation. Note that symbols (e.g. Greek letters) may not transmit properly in this form due to potential software compatibility issues. Please spell out the words in place of the symbols (e.g. replace “α” with “alpha”). Comments should be no more than 8,000 characters (including spaces ) in length. References may be included when necessary but should be kept to a minimum. Be careful if copying and pasting from a Word document. Smart quotes can cause problems in the form. If you experience difficulties, please convert to a plain text file and then copy and paste into the form.