Resistance to Experimental Autoimmune Encephalomyelitis and Impaired IL-17 Production in Protein Kinase Cθ-Deficient Mice

Tan, Seng‐Lai; Zhao, Jingyong; Bi, Chen; Chen, Xinyi Cynthia; Hepburn, Deena L.; Wang, Jian; Sedgwick, Jonathon D.; Chintalacharuvu, Subba R.; Na, Songqing

doi:10.4049/jimmunol.176.5.2872

Cited by 130 publications

(117 citation statements)

References 40 publications

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“…The latter is consistent with the observation that PKCy-deficient mice are resistant to EAE and have reduced IL-17 in the CNS [69]. Furthermore, studies in patients with rheumatoid arthritis have suggested that overproduction of IL-17 is dependent on signal transduction pathways involving PI3K/Akt and NF-kB [70].…”

Section: Intracellular Signalling Molecules and Transcription Factorssupporting

confidence: 87%

Induction, function and regulation of IL‐17‐producing T cells

2008

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Recent reports have provided convincing evidence that IL-17-producing T cells play a key role in the pathogenesis of organ-specific autoimmune diseases, a function previously attributed exclusively to IFN-c-secreting Th1 cells. Furthermore, it appears that IL-17-producing T cells can also function with Th1 cells to mediate protective immunity to pathogens. Although much of the focus has been on IL-17-secreting CD4 1 T cells, termed The main function of IL-17-secreting T cells is to mediate inflammation, by stimulating production of inflammatory cytokines, such as TNF-a, IL-1b and IL-6, and inflammatory chemokines that promote the recruitment of neutrophils and macrophages.Key words: Autoimmunity . IL-17 . Infection . Inflammation IntroductionMore than 20 years ago Mosmann and Coffman reported that distinct CD4 1 T-cell subtypes, termed Th1 and Th2 cells, could be distinguished on the basis of cytokine secretion and function [1]. The Th1-Th2 model provided a useful but simplistic basis for our understanding of the mechanisms of immunity to infection and also attempted to explain the role of T cells in the pathogenesis of autoimmunity and allergy/asthma. The original hypothesis was that IFN-g-secreting CD4 1 cells mediated protective immunity to intracellular pathogens by promoting macrophage activation and stimulating production of complement fixing and virus neutralizing antibodies, but also promoted inflammatory responses and mediated the pathology in certain autoimmune diseases. In contrast, CD4 1 T cells that secreted IL-4, IL-5, IL-10 and IL-13 were considered to be the main helper T cells providing help for B-cell production of antibody, especially IgG1 in mice, and mediated protective immunity to extracellular pathogens. These Th2 cells were also anti-inflammatory, controlling Th1 responses, but at the same time mediated allergic reactions and had an inflammatory and pathological role in asthma.The identification of additional T-cell subtypes has led to a shift in the Th1-Th2 paradigm and has helped to explain some anomalies in the original model. In the mid 1990s suppressor T cells were re-discovered as Treg cells and were shown to have a major role in controlling immune responses to self-antigens, thereby preventing autoimmunity. Furthermore, these cells rather than the reciprocal Th1 or Th2 populations were shown to be the major regulator of effector T cells, functioning to maintain self-tolerance, prevent autoimmunity and limit collateral damage during immune responses to pathogens [2,3].There were a number of other observations which could not be explained on the basis of the two Th1 and Th2 subtypes. Mini-ReviewDespite the assumption that Th1 cells mediated autoimmunity, mice deficient in IFN-g or IFN-g receptors were found to have increased susceptibility to EAE and collagen-induced arthritis (CIA) [4,5]. Furthermore, EAE was exacerbated in mice deficient in the Th1 polarizing cytokine, 7]. It was then discovered that mice deficient in the novel IL-12 family member, IL-23 were resistant to EAE [6]....

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Section: Intracellular Signalling Molecules and Transcription Factorssupporting

confidence: 87%

Induction, function and regulation of IL‐17‐producing T cells

2008

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“…However, the relevance of PKC -induced JNK activation remains unclear, as mature T cells from PKC knockouts displayed intact JNK function (33). Moreover, PKCdeficient mice have been shown to be resistant to EAE and are unable to mount Th1-type responses (34,35). Thus, we conclude that the reduced encephalitogenic potential and attenuated Th1-type responses of PLP-specific T cells after Notch3 inhibition may result from PKC activation.…”

Section: Discussionmentioning

confidence: 91%

Notch3 Inhibition in Myelin-Reactive T Cells Down-Regulates Protein Kinase Cθ and Attenuates Experimental Autoimmune Encephalomyelitis

Juryńczyk

Jurewicz

Raine

et al. 2008

The Journal of Immunology

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Among its varied functions, Notch signaling is involved in peripheral T cells responses. The activation and polarization of CD4+ T cells toward a Th1 lineage are essential steps in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Inhibition of all four Notch receptors with a γ-secretase inhibitor was shown to block Th1-type polarization and to attenuate the symptoms of experimental autoimmune encephalomyelitis. In this study, we have examined the role of individual Notch receptors in proliferation, cytokine production, and encephalitogenic potential of PLP-reactive T cells. Specific induction of Notch1 and Notch3 transcripts were noted in PLP-reactive T cells upon Ag stimulation. However, using γ-secretase inhibitor and Abs blocking distinct Notch receptors, we have found that selective inhibition of Notch3, but not Notch1, receptor abrogated proliferation, Th1- and Th17-type responses of PLP-reactive T cells. Moreover, Notch3 inhibition in T cells correlated with the down-regulated expression of protein kinase Cθ, a kinase with important regulatory function within mature T cells. Thus, selective inhibition of the Notch3 receptor may have important effects on peripheral T cell responses and may offer a new attractive target in treating autoimmune diseases, including multiple sclerosis.

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“…16 PKC--deficient mice develop less severe neurologic signs in T-cell-dependent experimental autoimmune encephalomyelitis models, with delayed CD4 ϩ T-cell recruitment and modulation of Th1 and Th17 cytokine profiles. 35,36 Moreover, they developed less severe Th1-dependent responses in antigen-induced arthritis. 37 To address the role of PKC-in CM pathogenesis, PKC--deficient mice were investigated for several aspects of the pathophysiology of CM development.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

Fauconnier

Bourigault

Même

et al. 2011

The American Journal of Pathology

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Cerebral malaria is the most severe neurologic complication in children and young adults infected with Plasmodium falciparum. T-cell activation is required for development of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (CM). To characterize the T-cell activation pathway involved, the role of protein kinase C-theta (PKC-) in experimental CM development was examined. PKC--deficient mice are resistant to CM development. In the absence of PKC-, no neurologic sign of CM developed after blood stage PbA infection. Resistance of PKC--deficient mice correlated with unaltered cerebral microcirculation and absence of ischemia, as documented by magnetic resonance imaging and magnetic resonance angiography, whereas wild-type mice developed distinct microvascular pathology. Recruitment and activation of CD8 ؉ T cells, and ICAM-1 and CD69 expression were reduced in the brain of resistant mice; however, the pulmonary inflammation and edema associated with PbA infection were still present in the absence of functional PKC-. Resistant PKC--deficient mice developed high parasitemia, and died at 3 weeks with severe anemia. Therefore, PKC-signaling is crucial for recruitment of CD8 ؉ T cells and development of brain microvascular pathology resulting in fatal experimental CM, and may represent a novel therapeutic target of CM.

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Resistance to Experimental Autoimmune Encephalomyelitis and Impaired IL-17 Production in Protein Kinase Cθ-Deficient Mice

Cited by 130 publications

References 40 publications

Induction, function and regulation of IL‐17‐producing T cells

Induction, function and regulation of IL‐17‐producing T cells

Notch3 Inhibition in Myelin-Reactive T Cells Down-Regulates Protein Kinase Cθ and Attenuates Experimental Autoimmune Encephalomyelitis

Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

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