The role of IFN-γ in immune responses to viral infections of the central nervous system

Chesler, David A.; Reiss, Carol Shoshkes

doi:10.1016/s1359-6101(02)00044-8

Cited by 159 publications

(131 citation statements)

References 169 publications

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“…IFNγ and, to a lesser extent IFNα, induce indoleamine-2,3-dioxygenase (IDO) in circulating immune cells, primarily macrophages. IDO converts tryptophan to kynurenine, which is subsequently converted to quinolinic acid [110]. Thus, administration of IFNγ, or induction of endogenous IFNγ secretion decreases plasma concentrations of tryptophan and increases plasma kynurenine.…”

Section: 52mentioning

confidence: 99%

Effects of cytokines and infections on brain neurochemistry

Dunn

2006

Clinical Neuroscience Research

278

169

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Administration of cytokines to animals can elicit many effects on the brain, particularly neuroendocrine and behavioral effects. Cytokine administration also alters neurotransmission, which may underlie these effects. The most well studied effect is the activation of the hypothalamopituitary-adrenocortical (HPA) axis, especially that by interleukin-1 (IL-1). Peripheral and central administration of IL-1 also induces norepinephrine (NE) release in the brain, most markedly in the hypothalamus. Small changes in brain dopamine (DA) are occasionally observed, but these effects are not regionally selective. IL-1 also increases brain concentrations of tryptophan, and the metabolism of serotonin (5-HT) throughout the brain in a regionally nonselective manner. Increases of tryptophan and 5-HT, but not NE, are also elicited by IL-6, which also activates the HPA axis, although it is much less potent in these respects than IL-1. IL-2 has modest effects on DA, NE and 5-HT. Like IL-6, tumor necrosis factor-α (TNFα) activates the HPA axis, but affects NE and tryptophan only at high doses. The interferons (IFN's) induce fever and HPA axis activation in man, but such effects are weak or absent in rodents. The reported effects of IFN's on brain catecholamines and serotonin have been very varied. However, interferon-γ, and to a lesser extent, interferon-α, have profound effects on the catabolism of tryptophan, effectively reducing its concentration in plasma, and may thus limit brain 5-HT synthesis.Administration of endotoxin (LPS) elicits responses similar to those of IL-1. Bacterial and viral infections induce HPA activation, and also increase brain NE and 5-HT metabolism and brain tryptophan. Typically, there is also behavioral depression. These effects are strikingly similar to those of IL-1, suggesting that IL-1 secretion, which accompanies many infections, may mediate these responses. Studies with IL-1 antagonists, support this possibility, although in most cases the antagonism is incomplete, suggesting the existence of multiple mechanisms. Because LPS is known to stimulate the secretion of IL-1, IL-6 and TNFα, it seems likely that these cytokines mediate at least some of the responses, but studies with antagonists indicate that there are multiple mechanisms. The neurochemical responses to cytokines are likely to underlie the endocrine and behavioral responses. The NE response to IL-1 appears to be instrumental in the HPA activation, but other mechanisms exist. Neither the noradrenergic nor the serotonergic systems appear to be involved in the major behavioral responses. The significance of the serotonin response is unknown.

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Section: 52mentioning

confidence: 99%

Effects of cytokines and infections on brain neurochemistry

Dunn

2006

Clinical Neuroscience Research

278

169

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“…This may be beneficial due to the fact that neurons do not replicate, and so a vigorous attack by the immune system on virally infected postmitotic neurons may cause more problems than the virus itself. In the brain, functional receptors for IFN-␥ are expressed in all cells, but they are expressed at different levels, and actions of IFN-␣/␤ on microglia, astrocytes, and neurons have also been described (12,13,31,43). Most cells, including astrocytes and microglia, are able to produce IFN-␣/␤ as an initial nonspecific immune response against virus infection (52,64); IFN-␥ is released by activated T lymphocytes as part of the specific immune response.…”

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confidence: 99%

Cytomegalovirus InducesInterferon-Stimulated Gene Expression and Is Attenuated by Interferon in the DevelopingBrain

Pol¹,

Robek

Ghosh³

et al. 2007

J Virol

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Cytomegalovirus (CMV) is considered the most common infectious agent causing permanent neurological dysfunction in the developing brain. We have previously shown that CMV infects developing brain cells more easily than it infects mature brain cells and that this preference is independent of the host B-and T-cell responses. In the present study, we examined the innate antiviral defenses against mouse (m) and human ( Cytomegalovirus (CMV), a double-stranded DNA virus of the betaherpesvirus family, is considered the most common infectious agent that causes permanent neurological dysfunction of the developing brain (2, 62). Human CMV (hCMV) infections in the developing brain can lead to mental retardation, epilepsy, microcephaly, microgyria, hydrocephalus, and deafness (4, 21, 37). The developing brain is particularly sensitive to CMV infection (6,29,54,55,58) due to both the immature state of the systemic immune system and a preference of CMV for developing glia and neurons (61). CMV in the mature brain is less of a concern, except in immunocompromised individuals (22,23,32).Outside the brain, interferon (IFN) has been reported to limit some CMV infections (27,30,66). A number of reports have suggested that brain cells differ from cells of other organs relative to innate and systemic antiviral immune responses. The brain has some characteristics of an immunologically privileged region. For instance, although most cells outside the brain express major histocompatibility complex (MHC) class I molecules, neurons in the brain either do not express MHC class I or do so at a substantially reduced level (45). This may be beneficial due to the fact that neurons do not replicate, and so a vigorous attack by the immune system on virally infected postmitotic neurons may cause more problems than the virus itself. In the brain, functional receptors for IFN-␥ are expressed in all cells, but they are expressed at different levels, and actions of IFN-␣/␤ on microglia, astrocytes, and neurons have also been described (12,13,31,43). Most cells, including astrocytes and microglia, are able to produce IFN-␣/␤ as an initial nonspecific immune response against virus infection (52, 64); IFN-␥ is released by activated T lymphocytes as part of the specific immune response. The intrinsic IFN system provides the first line of defense against viral infections, including systemic CMV infections, and can delay viral replication allowing the activation of the systemic adaptive immune responses.One explanation for the increased pathogenesis in the developing brain compared to that in the mature brain is that the systemic immune system is too immature during development to fight CMV infection. T and B lymphocytes of the adaptive immune system, as well as other cells of the systemic immune system, including natural killer cells and macrophages/monocytes, are involved in combating CMV infections (2,5,8,9,10,20,46,49), and the efficacies of these systems increase with development. Another mechanism that might underlie the susceptibility of developing...

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“…40 An IFN-␥-dependent immune response further increases the local accumulation of activated immune cells and mediates the tissue damage of the CNS. [41][42][43][44] Phenotypically, these GF-IL12 transgenic mice develop a severe cerebellitis and, correspondingly, progressive ataxia. 25 However, most GF-IL12/CXCR3KO mice did not develop a clinical phenotype and had only minor histopathologic alterations of the cerebellum.…”

Section: Discussionmentioning

confidence: 99%