Enhanced Production of IL-10 by Dendritic Cells Deficient in CIITA

Yee, Christina S.K.; Yao, Yongxue; Xu, Qi; McCarthy, Brian P.; Sun-Lin, Deqin; Tone, Masahide; Waldmann, Herman; Chang, Cheong Hee

doi:10.4049/jimmunol.174.3.1222

Cited by 48 publications

(41 citation statements)

References 47 publications

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“…This suggests that CIITA is highly dedicated to the regulation of MHC-II expression. Nevertheless, a series of reports have implicated CIITA in the regulation of a wide variety of other genes functioning within and outside the immune system [8][9][10][11][12][13][14]20]. These reports suggested that CIITA might play a pleiotropic role in various biological processes.…”

Section: Discussionmentioning

confidence: 99%

“…The genes encoding IL-4 and Fas ligand (FasL) were proposed to be repressed by CIITA in mouse T cells [8,9]. Those encoding cathepsin E and IL-10 were suggested to be repressed by CIITA in mouse B cells and/or DC [10,11]. The genes encoding collagen type Ia2, thymidine kinase and cyclin D1 were proposed to be repressed by CIITA in IFN-c-induced cells [12].…”

Section: Molecular Immunologymentioning

confidence: 99%

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Revisiting the specificity of the MHC class II transactivator CIITA in vivo

Otten¹,

LeibundGut‐Landmann²,

Huarte³

et al. 2006

Eur J Immunol

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CIITA is a master regulatory factor for the expression of MHC class II (MHC-II) and accessory genes involved in Ag presentation. It has recently been suggested that CIITA also regulates numerous other genes having diverse functions within and outside the immune system. To determine whether these genes are indeed relevant targets of CIITA in vivo, we studied their expression in CIITA-transgenic and CIITA-deficient mice. In contrast to the decisive control of MHC-II and related genes by CIITA, nine putative non-MHC target genes (Eif3s2, Kpna6, Tap1, Yars, Col1a2, Ctse, Ptprr, Tnfsf6 and Plxna1) were found to be CIITA independent in all cell types examined. Two other target genes, encoding IL-4 and IFN-c, were indeed found to be up-and down-regulated, respectively, in CIITA-transgenic CD4 + T cells. However, there was no correlation between MHC-II expression and this Th2 bias at the level of individual transgenic T cells, indicating an indirect control by CIITA. These results show that MHC-II-restricted Ag presentation, and its indirect influences on T cells, remains the only pathway under direct control by CIITA in vivo. They also imply that precisely regulated MHC-II expression is essential for maintaining a proper Th1-Th2 balance.

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Section: Discussionmentioning

confidence: 99%

Section: Molecular Immunologymentioning

confidence: 99%

Revisiting the specificity of the MHC class II transactivator CIITA in vivo

Otten¹,

LeibundGut‐Landmann²,

Huarte³

et al. 2006

Eur J Immunol

View full text Add to dashboard Cite

show abstract

“…The list of transcription factors that activate IL10 production is increasing; however, only a handful of transcription factors are known to repress its expression (23). Transcription factors ETS1 and T-bet repress IL10 expression in Th1 cells, BCL-6 inhibits IL10 production in Th2 cells, MHC class II transactivator (CIITA) negatively regulates IL10 expression in mouse dendritic cells, and BCL-3 represses IL10 production in macrophages (23,(45)(46)(47)(48). However, the quest for master regulators with a direct binding site on the IL10 promoter still remains.…”

Section: Discussionmentioning

confidence: 99%

Human IL10 Gene Repression by Rev-erbα Ameliorates Mycobacterium tuberculosis Clearance

Chandra

Mahajan

Saini

et al. 2013

Journal of Biological Chemistry

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Background: Transcriptional modulation of IL10, a cytokine that blocks phagolysosome maturation, is not well understood. Results: This study demonstrates human IL10 gene repression by direct binding of Rev-erb␣ on Rev-DR2 in the proximal promoter. Conclusion: Rev-erb␣ binds to IL10 proximal promoter, represses expression, and impedes Mycobacterium tuberculosis in human macrophages. Significance: This study provides rationale to target Rev-erb␣ as a therapeutic intervention that might support host defense in tuberculosis.Nuclear receptors modulate macrophage effector functions, which are imperative for clearance or survival of mycobacterial infection. The adopted orphan nuclear receptor Rev-erb␣ is a constitutive transcriptional repressor as it lacks AF2 domain and was earlier shown to be present in macrophages. In the present study, we highlight the differences in the relative subcellular localization of Rev-erb␣ in monocytes and macrophages. The nuclear localization of Rev-erb␣ in macrophages is subsequent to monocyte differentiation. Expression analysis of Rev-erb␣ elucidated it to be considerably more expressed in M1 phenotype in comparison with M2. Rev-erb␣ overexpression augments antimycobacterial properties of macrophage by keeping IL10 in a basal repressed state. Further, promoter analysis revealed that IL10 promoter harbors a Rev-erb␣ binding site exclusive to humans and higher order primates and not mouse, demonstrating a species barrier in its functionality. This direct gene repression is mediated by recruitment of co-repressors NCoR and HDAC3. In addition, our data elucidate that its overexpression reduced the survival of intracellular pathogen Mycobacterium tuberculosis by enhancing phagosome lysosome maturation, an event resulting from IL10 repression. Thus, these findings suggest that Rev-erb␣ bestows protection against mycobacterial infection by direct gene repression of IL10 and thus provide a novel target in modulating macrophage microbicidal properties.Macrophages are immune system sentinels with a major role to play in both innate and adaptive immunity. They are the key effectors in antimicrobial defense, atherogenesis, autoimmunity, and many other inflammatory diseases (1). Although the activation, function, classification, and plasticity of these cells have been studied extensively with regard to cellular signaling, the cytokine environment, and surface, cellular, or secretory markers, studies of the underlying molecular mechanism have mostly addressed NF-B (2). Similarly, modulation of macrophage function and alteration of disease pathology by small molecules such as heme, lipids, or drugs such as rifampicin are well understood at the translational level of the effectors (3, 4), but the transcriptional mechanism involving interactions of these ligands with transcriptional molecules and the resulting expression patterns have not been investigated.This study focuses on Rev-erb␣, an adopted orphan nuclear receptor that belongs to the steroid/thyroid hormone receptor superfamily and is a known ...

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“…T2 and Priess, provided by Dr. J. Blum (Indiana University, Indianapolis, IN), were grown in IMDM with the same supplements. Mouse splenic B cells were prepared as described previously (34).…”

Section: Cellsmentioning

confidence: 99%