Transcriptional regulation of Th1/Th2 polarization

Rengarajan, Jyothi; Szabo, Susanne J.; Glimcher, Laurie H.

doi:10.1016/s0167-5699(00)01712-6

Cited by 389 publications

(294 citation statements)

References 38 publications

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“…Because our results indicate that the NAC-induced increases in IL-4 are independent of STAT6, other transcription factors relevant to IL-4 expression were evaluated. Both AP-1 and NFATc2 have been positively linked to IL-4 production (16,36,37). When we evaluated the effect of NAC on AP-1 DNA binding and NFATc2 nuclear translocation, we found that NAC caused a significant increase in the activation of both transcription factors.…”

Section: Discussionmentioning

confidence: 90%

“…The NFAT proteins are a family of transcription factors (NFATc1, NFATc2, and NFATc3) that are present in both Th1 and Th2 cells. In Th2 cells, NFAT proteins have been shown to act cooperatively with additional transcription factors, such as AP-1, and NF B, to enhance IL-4 gene expression (16). To evaluate the effect of NAC on the nuclear expression of these transcription factors, untreated or ␣CD3-treated naive splenocytes were cultured in the presence or the absence of 15 mM NAC for 45 min.…”

Section: Nac Increases Nuclear Translocation Of Il-4 Relevant Transcrmentioning

confidence: 99%

“…Both Th1-and Th2-specific cytokines promote the growth or differentiation of their own respective T cell subsets. It has been shown that IL-12 and IL-4 play a dominant role in differentiation of Th1 and Th2 cells, respectively (15,16). Conditions (other than cytokines themselves) that predispose the development of Th1 vs Th2 responses are not entirely clear.…”

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confidence: 99%

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Intracellular Thiols Contribute to Th2 Function via a Positive Role in IL-4 Production

Monick

Samavati

Butler

et al. 2003

The Journal of Immunology

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A number of lung diseases, including many interstitial lung diseases and HIV infection, are associated with decreases in intracellular thiols. Altered Th1/Th2 T cell balance has also been associated with disease progression in many of the same diseases. IFN-γ and IL-4 are critical effector cytokines of Th1 and Th2 cells, respectively. To determine the effect of thiols on the production of IFN-γ and IL-4 by splenocytes, cells were incubated in the presence and the absence of N-acetylcysteine (NAC) and stimulated with αCD3 or αCD3 and IL-12. Augmenting intracellular soluble thiol pools (∼2-fold) with 15 mM NAC blocked induction of IFN-γ and increased production of IL-4 without causing significant changes in intracellular glutathione levels. The effect of NAC on IL-4 production was not linked to an increase in STAT6 phosphorylation, as STAT6 levels were decreased, nor did the increase in IL-4 occur with purified CD4 cells. We found that NAC increased splenocyte IL-4 production via an effect on APCs. We also found that NAC increased two IL-4 relevant transcription factors (AP-1) and NFATc. These studies suggest that increasing intracellular reduced thiol pools decreases IL-12 signaling and IFN-γ production, while increasing IL-4 production. The sum of these effects may contribute to alterations in the balance between Th1 and Th2 responses in lung diseases associated alterations in intracellular thiol pools.

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Section: Discussionmentioning

confidence: 90%

Section: Nac Increases Nuclear Translocation Of Il-4 Relevant Transcrmentioning

confidence: 99%

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Intracellular Thiols Contribute to Th2 Function via a Positive Role in IL-4 Production

Monick

Samavati

Butler

et al. 2003

The Journal of Immunology

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“…Merika and Orkin, (1993) demonstrated that DNA strands containing the core sequence AGATAT (the reverse orientation of the A allele) bound human GATA-3, while zero of 63 sequences shown to bind GATA-3 contained the core sequence AGACAT (the reverse orientation of the G allele). GATA-3 is an important transcription factor directing the polarisation of naïve T cells to Th-2 cells (Rengarajan et al, 2000). 1a,25-dihydroxyvitamin D 3 has been shown to upregulate GATA-3 gene expression and the GATA-3 protein promotes polarisation to Th-2 (Boonstra et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

A novel polymorphism in the 1A promoter region of the vitamin D receptor is associated with altered susceptibilty and prognosis in malignant melanoma

et al. 2004

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The association of Taq 1 and Fok 1 restriction fragment length polymorphisms of the vitamin D receptor with occurrence and outcome of malignant melanoma (MM), as predicted by tumour (Breslow) thickness, has been reported previously. We now report a novel adenine -guanine substitution À1012 bp relative to the exon 1a transcription start site (A-1012G), found following screening by single-stranded conformational polymorphism of this promoter region. There was a total of 191 MM cases , which were stratified according to conventional Breslow thickness groups, cases being randomly selected from each group to form a distribution corresponding to the known distribution of Breslow thickness in our area, and this population (n ¼ 176) was compared to 80 controls. The A allele was over-represented in MM patients and, with GG as reference, odds ratio (OR) for AG was 2.5, 95% confidence interval (CI) 1.1 -5.7, (P ¼ 0.03) and AA 3.3, CI 1.4 -8.1, (P ¼ 0.007). The outcome was known in 171 of 191 patients and the A allele was related to the development of metastasis, the Kaplan -Meier estimates of the probability of metastasis at 5 years being: GG 0%; AG 9%, CI 4 -16%; AA 21%, CI 12 -36%; (P ¼ 0.008), and to thicker Breslow thickness groups (P ¼ 0.04). The effect on metastasis was independent of tumour thickness and A-1012G may have predictive potential, additional to Breslow thickness. Neither the Fok 1 nor Taq 1 variants (f and t) were significantly related to the development of metastasis, although there was a strong relationship of fftt with the thickest Breslow thickness group (P ¼ 0.005). There was an interaction between the A-1012G and Fok 1 polymorphisms (P ¼ 0.025) and the Fok 1 variant enhanced the effect of the A allele of the A-1012G polymorphism on metastasis, the probability of metastasis for AAff at 5 years follow-up being 57%, CI 24 -92%.

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“…Several genes that are critical for these responses are directly regulated by STAT6, and e.g. the promoter regions of Ig heavy chain germline Ig⑀ and Ig␥1, CD23, and major histocompatibility complex class II promoters contain functional STAT6 response elements (3)(4)(5).…”

mentioning

confidence: 99%

The Transcriptional Co-activator Protein p100 Recruits Histone Acetyltransferase Activity to STAT6 and Mediates Interaction between the CREB-binding Protein and STAT6

Välineva

Yang

Palovuori

et al. 2005

Journal of Biological Chemistry

113

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STAT6 is a critical regulator of transcription for interleukin-4 (IL-4)-induced genes. Activation of gene expression involves recruitment of coactivator proteins that function as bridging factors connecting sequence-specific transcription factors to the basal transcription machinery, and as chromatin-modifying enzymes. Coactivator proteins CBP/p300 have been implicated in regulation of transcription in all STATs. CBP is also required for STAT6-mediated gene activation, but the underlying molecular mechanisms are still elusive. In this study we investigated the mechanisms by which STAT6 recruits CBP and chromatin-modifying activities to the promoter. Our results indicate that while STAT1-interacted directly with CBP, the interaction between STAT6 and CBP was found to be mediated through p100 protein, a coactivator protein that has previously been shown to stimulate the transcription of IL-4-induced genes. The staphylococcal nuclease-like (SN)-domains of p100 directly interacted with amino acids 1099 -1758 of CBP, while p100 did not associate with SRC-1, another coactivator of STAT6. p100 was found to recruit histone acetyltransferase (HAT) activity to STAT6 in vivo. Chromatin immunoprecipitation studies demonstrated that p100 increases the STAT6-p100-CBP ternary complex formation in the human Ig⑀ promoter. p100 also increased the amount of acetylated histone H4 at the Ig⑀ promoter, and siRNAs directed against p100 effectively inhibited Ig⑀ reporter gene expression. Our results suggest that p100 has an important role in the assembly of STAT6 transcriptosome, and that p100 stimulates IL-4-dependent transcription by mediating interaction between STAT6 and CBP and recruiting chromatin modifying activities to STAT6-responsive promoters.Signal transducer and activator of transcription (STAT) 1 family of transcription factors convert extracellular cytokine signals into diverse biological responses through modulation of gene transcription (1). Cytokines bind to their cognate receptors at the cell surface, which leads to the activation of receptor-associated JAK kinases, which in turn activate STATs by phosphorylating them at the conserved C-terminal tyrosine residue. The activated STATs undergo dimerization through a reciprocal SH2-phosphotyrosine interaction and translocate to the nucleus, where the STAT dimers bind to symmetrical TTC(N 2-4 )GAA DNA target elements. The specificity in cytokine signaling is conveyed by selective activation of different STATs by individual cytokine receptors, specific recognition of target DNA elements by various STATs, and through selective interaction and cooperation with other transcription factors and regulatory proteins.The family of STAT proteins consists of seven members that mediate highly specific functions in cytokine signaling. STAT6 is mediating interleukin-4 (IL-4)-and IL-13-induced gene responses (2). IL-4 is an important regulator of immune and anti-inflammatory responses. In T cells IL-4 mediates induction of Th2 differentiation, while inhibiting Th1 development, and in B ...

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Transcriptional regulation of Th1/Th2 polarization

Cited by 389 publications

References 38 publications

Intracellular Thiols Contribute to Th2 Function via a Positive Role in IL-4 Production

Intracellular Thiols Contribute to Th2 Function via a Positive Role in IL-4 Production

A novel polymorphism in the 1A promoter region of the vitamin D receptor is associated with altered susceptibilty and prognosis in malignant melanoma

The Transcriptional Co-activator Protein p100 Recruits Histone Acetyltransferase Activity to STAT6 and Mediates Interaction between the CREB-binding Protein and STAT6

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