Enhanced Sensitivity of Tumor Necrosis Factor/Lymphotoxin‐α–Deficient Mice toCryptococcus neoformansInfection despite Increased Levels of Nitrite/Nitrate, Interferon‐γ, and Interleukin‐12

Abstract

The cytokine network and infection severity were characterized during disseminated cryptococcosis in tumor necrosis factor (TNF)- and lymphotoxin (Lt)-alpha-deficient mice. On day 16, the fungus burden was higher and median survival time was reduced, as was polymorphonuclear leukocyte infiltrate in the brains of knockout mice. TNF/Lt-alpha-deficient mice had lower levels of interleukin (IL)-6 in lungs and brains, IL-1beta, and the chemokine KC in brain and spleen and of the chemokine monocyte chemoattractant protein (MCP)-1 in spleen than control animals. In contrast, higher levels of IL-6, IL-10, and MCP-1 in plasma and higher levels of IL-12, interferon (IFN)-gamma, and nitrite/nitrate were found in all compartments of TNF/Lt-alpha-deficient mice. These data confirm that TNF or Lt-alpha is a key cytokine for the anticryptococcal response and demonstrate its major role for the induction of IL-1beta, IL-6, and KC in the brain; however, its presence is not a prerequisite for IL-12, IFN-gamma, and nitrite/nitrate production.

Induction of Interleukin-12 and Gamma Interferon Requires Tumor Necrosis Factor Alpha for Protective T1-Cell-Mediated Immunity to PulmonaryCryptococcus neoformansInfection

“…TNF-␣ and IL-12 production by macrophages is also required for IFN-␥ production during Listeria monocytogenes infection (36), while neutralization of TNF-␣ with a soluble TNF receptor fusion protein can inhibit Th1 polarization in vitro through the inhibition of IL-12 and IFN-␥ (2). In contrast, a report by Rayhane et al has shown that TNF-␣ is not required for induction of IFN-␥ and IL-12 during C. neoformans infection (30). However, these differences are almost certainly due to different routes of infection (intravenous versus intratracheal), kinetics of cytokine analysis (day 16 versus day 7), and sites analyzed.…”

In the Absence of Reactive Oxygen Species, T Cells Default to a Th1 Phenotype and Mediate Protection against Pulmonary Cryptococcus neoformans Infection

“…TNF-␣ in Cybb tm1 mice may assist in the maintenance of a protective Th1 response. TNF knockout mice are more susceptible to C. neoformans infection (55), and Huffnagle and colleagues (56,57) have demonstrated a significant early role for TNF in leukocyte recruitment of leukocytes and the development of Th1-biased immune response. Indeed, we have previously reported that CpG has been demonstrated to promote a heightened Th1 response to C. neoformans and prevent dissemination to the brain, an effect that was abolished by depleting TNF-␣ (58).…”

Role of Capsule and Interleukin-6 in Long-Term Immune Control ofCryptococcus neoformansInfection by Specifically Activated Human Peripheral Blood Mononuclear Cells

“…A CNS-specific and TNF-␣-dependent role for IL-6 and IL-1␤ in protection against cryptococcosis is suggested by findings with TNF/lymphotoxin-␣-deficient mice. The markedly reduced survival of TNF/lymphotoxin-␣-deficient mice was associated with a marked reduction in brain levels of IL-6 and IL-1␤, while levels of these cytokines in plasma and other organs were similar in knockout and parental-strain mice, and plasma and tissue levels of IFN-␥ and IL-12 were higher in knockout than in parentalstrain mice (28).…”