Tumor Necrosis Factor Alpha-Mediated Toxic Shock inTrypanosoma cruzi-Infected Interleukin 10-Deficient Mice

Abstract

Using interleukin-10 (IL-10)-deficient (IL-10؊/؊ ) mice, previous studies revealed a pathological immune response after infection with Trypanosoma cruzi that is associated with CD4؉ T cells and overproduction of proinflammatory cytokines. In this study we further investigate the pathology and potential mediators for the mortality in infected animals. T. cruzi-infected IL-10 ؊/؊ mice showed reduced parasitemia accompanied by increased systemic release of gamma interferon (IFN-␥), IL-12, and reactive nitrogen intermediates and overproduction of tumor necrosis factor alpha (TNF-␣). Despite this early resistance, IL-10 ؊/؊ mice died within the third week of infection, whereas all control mice survived acute infection. The clinical manifestation with weight loss, hypothermia, hypoglycemia, hyperkalemia, and increased liver-derived enzymes in the blood together with hepatic necrosis and intravascular coagulation in moribund mice indicated a toxic shock-like syndrome, possibly mediated by the systemic TNF-␣ overproduction. Indeed, high production of systemic TNF-␣ significantly correlated with mortality, and moribund mice died with critically high TNF-␣ concentrations in the blood. Consequent treatment with anti-TNF-␣ antiserum attenuated pathological changes in T. cruzi-infected IL-10 ؊/؊ mice and significantly prolonged survival; the mice died during the fourth week postinfection, again with a striking correlation between regaining high systemic TNF-␣ concentrations and the time of death. Since elevated serum IL-12 and IFN-␥ concentrations were not affected by the administration of antiserum, these studies suggest that TNF-␣ is the direct mediator of this toxic shock syndrome. In conclusion, induction of endogenous IL-10 during experimentally induced Chagas' disease seems to be crucial for counterregulating an overshooting proinflammatory cytokine response resulting in TNF-␣-mediated toxic shock.

Pathology ofPlasmodium chabaudi chabaudiInfection and Mortality in Interleukin-10-Deficient Mice Are Ameliorated by Anti-Tumor Necrosis Factor Alpha and Exacerbated by Anti-Transforming Growth Factor β Antibodies

“…Although there is no significant difference in the course of parasitemia, up to 50% of female IL-10 Ϫ/Ϫ mice die within 17 days and the infection is associated with more severe weight loss, hypoglycemia, and hypothermia than usually observed in C57BL/6 or other resistant strains of mice (18,20). These data suggest that the severe pathological changes and increased mortality in P. chabaudi-infected IL-10 Ϫ/Ϫ mice might be the result of the enhanced inflammatory responses, as is the case for Trypanosoma cruzi and Toxoplasma gondii infections in these mice (5,9,11). A clear relationship between IFN-␥ and malaria-related pathology could not be demonstrated in P. chabaudi infections of IL-10 Ϫ/Ϫ mice (18), although removal of IFN-␥ by antibodies and gene targeting of the IFN-␥ receptor did rescue IL-10 Ϫ/Ϫ mice from an otherwise lethal infection (18).…”

Endogenous glucocorticoids cause thymus atrophy but are protective during acute Trypanosoma cruzi infection

“…It is known that TNF-a levels are increased during the immune response to T. cruzi (Revelli et al 1999, Truyens et al 1999, Holscher et al 2000, Roggero et al 2002 and it is likely that this cytokine is also involved in the immunopathological processes during the disease (Truyens et al 1995, Holscher et al 2000. On the other hand, TNF-a and IL-6 can also activate the HPA-axis (Bernardini et al 1990, Besedovsky et al 1991.…”

IL-10 Is Required for Optimal CD8 T Cell Memory followingListeria monocytogenesInfection

“…Accordingly, IL-10 deficiency improves resistance to infection, as shown by studies using a variety of intracellular pathogens which include Listeria monocytogenes (2)(3)(4)(5)(6), Mycobacterium species (7-10), and Leishmania major (11,12). With some infectious agents, such as Toxoplasma gondii (13,14), Plasmodium chaubudi (15), or some strains of Trypanosoma cruzi (16,17), there is an increase in the frequency of effector CD4 T cells in IL-10-deficient mice, resulting in immunopathology in the form of a toxic shocklike syndrome from overproduction of Th1 cytokines. Finally, IL-10 has been shown to have a role in maintaining Th1 responses sufficient to mediate protection against the persistent pathogen, L. major (12,18).…”