IL-4 has been extensively studied in the context of its role in immunity. Accumulating evidence indicates, however, that it also plays a critical role in higher functions of the normal brain, such as memory and learning. In this review, we summarize current knowledge of the basic immunology of IL-4, describe how and where this cytokine appears to operate in normal brain function, and propose a hypothesis concerning its potential role in neurological pathologies. The Journal of Immunology, 2012, 189: 4213-4219.
"Cytokines may also interfere with the metabolism of neurotransmitters, such as serotonin and dopamine, in determined brain regions (amygdala, hippocampus, and nucleus accumbens) involved in the regulation of emotion, reward, and psychomotor functions  . Indeed both proinflammatory cytokines can stimulate the enzyme indoleamine 2,3-dioxygenase (IDO) . IDO converts tryptophan into kynurenine (KYN), reducing the availability of this precursor of serotonin [22– 26]. "
[Show abstract][Hide abstract] ABSTRACT: Bipolar disorder (BD) is a severe, chronic, and recurrent psychiatric illness. It has been associated with high prevalence of medical comorbidities and cognitive impairment. Its neurobiology is not completely understood, but recent evidence has shown a wide range of immune changes. Cytokines are proteins involved in the regulation and the orchestration of the immune response. We performed a review on the involvement of cytokines in BD. We also discuss the cytokines involvement in the neuroprogression of BD. It has been demonstrated that increased expression of cytokines in the central nervous system in postmortem studies is in line with the elevated circulating levels of proinflammatory cytokines in BD patients. The proinflammatory profile and the immune imbalance in BD might be regarded as potential targets to the development of new therapeutic strategies.
"The prototypical cytokine used to first induce alternative activation was IL-4 . Both IL-4 and the closely related cytokine IL-13 signal through IL-4Rα to induce a host of downstream processes that lead to potent anti-inflammatory functions, such as Arg1 upregulation, inhibition of NF-κB isoforms, and production of scavenger receptors for phagocytosis [19,47,48]. This type of activation has been classified as ‘M2a’. "
[Show abstract][Hide abstract] ABSTRACT: The concept of multiple macrophage activation states is not new. However, extending this idea to resident tissue macrophages, like microglia, has gained increased interest in recent years. Unfortunately, the research on peripheral macrophage polarization does not necessarily translate accurately to their central nervous system (CNS) counterparts. Even though pro- and anti-inflammatory cytokines can polarize microglia to distinct activation states, the specific functions of these states is still an area of intense debate. This review examines the multiple possible activation states microglia can be polarized to. This is followed by a detailed description of microglial polarization and the functional relevance of this process in both acute and chronic CNS disease models described in the literature. Particular attention is given to utilizing M2 microglial polarization as a potential therapeutic option in treating diseases.
Journal of Neuroinflammation 06/2014; 11(1):98. DOI:10.1186/1742-2094-11-98 · 5.41 Impact Factor
"For example glioma cells produce cytokines, such as IL-10, IL-4, IL-6, TGFβ and prostaglandins E2 (Rolle et al., 2012). These factors are able to activate microglial cells; in particular, IL-4 causes alternative activation (M2) of microglia (Gadani et al., 2012). Moreover, interactions between microglia and tumor cells are bi-directional (Galvão et al., 2013); under the influence of glioma, microglia release several classes of molecules that foster glioma growth, progression and inflammatory activation (Li and Graeber, 2012). "
[Show abstract][Hide abstract] ABSTRACT: Malignant gliomas are primary brain tumors characterized by morphological and genetic complexities, as well as diffuse infiltration into normal brain parenchyma. Within gliomas, microglia/macrophages represent the largest tumor-infiltrating cell population, contributing by at least one third to total tumor mass. Bi-directional interactions between glioma cells and microglia may therefore play an important role on tumor growth and biology. In the present study, we have characterized the influence of glioma soluble factors on microglial function, comparing the effects of media harvested under basal conditions to those of media obtained after inducing a pro-inflammatory activation state in glioma cells. We found that microglial cells undergo a different pattern of activation depending on the stimulus; in the presence of activated glioma-derived factors (LI-CM), i.e. a condition mimicking the late stage of pathology, microglia presents as a mixture of polarization phenotypes (M1 and M2a/b), with up-regulation of iNOS, IL-10 and ARG. At variance, microglia exposed to basal glioma-derived factors (C-CM), i.e. a condition resembling the early stage of pathology, shows a more specific pattern of activation, with increased M2b polarization status and up-regulation of IL-10 only. As far as viability and cell proliferation are concerned, both LI-CM and C-CM induce similar effects on microglial morphology. Finally, in human glioma tissue obtained from surgical resection of patients with IV grade glioblastoma, we detected a significant amount of CD68 positive cells, which is a marker of macrophage/microglial phagocytic activity, suggesting that in vitro findings presented here might have a relevance in the human pathology as well.
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