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INTERLEUKIN 4 ISOFORM 1
LATEST LITERATURE
1: European journal of immunology, 2010 Aug 16, 5(8)
Control of Schistosoma mansoni egg-induced inflammation by IL-4-responsive CD4(+)CD25(-)CD103(+)Foxp3(-) cells is IL-10-dependent.
[Abstract]Host protection to helminth infection requires IL-4 receptor alpha chain (IL-4Ralpha) signalling and the establishment of finely regulated Th2 responses. In the current study, the role of IL-4Ralpha-responsive T cells in Schistosoma mansoni egg-induced inflammation was investigated. Egg-induced inflammation in IL-4Ralpha-responsive BALB/c mice was accompanied with Th2-biased responses, whereas T-cell-specific IL-4Ralpha-deficient BALB/c mice (iLck(cre)Il4ra(-) (/lox)) developed Th1-biased responses with heightened inflammation. The proportion of Foxp3(+) Treg in the draining LN of control mice did not correlate with the control of inflammation and was reduced in comparison to T-cell-specific IL-4Ralpha-deficient mice. This was due to IL-4-mediated inhibition of CD4(+)Foxp3(+) Treg conversion, demonstrated in adoptively transferred Rag2(-) (/) (-) mice. Interestingly, reduced footpad swelling in Il4ra(-) (/lox) mice was associated with the induction of IL-4 and IL-10-secreting CD4(+)CD25(-)CD103(+)Foxp3(-) cells, confirmed in S. mansoni infection studies. Transfer of IL-4Ralpha-responsive CD4(+)CD25(-)CD103(+) cells, but not CD4(+)CD25(high) or CD4(+)CD25(-)CD103(-) cells, controlled inflammation in iLck(cre)Il4ra(-) (/lox) mice. The control of inflammation depended on IL-10, as transferred CD4(+)CD25(-)CD103(+) cells from IL-10-deficient mice were not able to effectively downregulate inflammation. Together, these results demonstrate that IL-4 signalling in T cells inhibits Foxp3(+) Treg in vivo and promotes CD4(+)CD25(-)CD103(+)Foxp3(-) cells that control S. mansoni egg-induced inflammation via IL-10.
2: Biochemical pharmacology, 2010 Aug 16, 131(1)
IL-4 mediated transcriptional regulation of human CYP2E1 by two independent signaling pathways.
[Abstract]Cytochrome P450 2E1 (CYP2E1), the alcohol-inducible member of the cytochrome P450 super family, plays an important role in both physiological and pathophysiological processes. The present study focused on the induction of human CYP2E1 transcription by the anti-inflammatory cytokine interleukin-4 (IL-4) in human hepatoma B16A2 cells and revealed that this regulation is mediated by two independent pathways. RNA interference and overexpression of STAT6, indicated that the JAK-STAT signaling pathway is involved in IL-4-dependent induction and mutagenesis revealed the presence of a STAT6 binding site in CYP2E1 proximal promoter region (-583/-574-bp). However, inhibition of the JAK-STAT6 pathway using JAK1 siRNA constructs could only partially inhibit the induction of CYP2E1 promoter constructs indicating the presence of a second IL-4 responsive element. Indeed by using a series of truncated CYP2E1 promoter constructs a second more distal IL-4 responsive element (-1604/-1428-bp) was identified, which was further shown to involve the activation of IRS1/2. This induction was dependent on the transcription factor NFATc1 as IL-4 induced CYP2E1 expression was altered by silencing or overexpressing NFATc1. A NFATc1 binding site was identified in the second distal IL-4 responsive element (-1551/-1545-bp) by chromatin immunoprecipitation (ChIP) analysis. Finally simultaneous siRNA mediated down-regulation of both STAT6 and NFATc1 or mutation of both STAT6 and NFATc1 binding sites abolished the IL-4-dependent transcriptional induction of CYP2E1, demonstrating that both pathways are required for maximal activation. In conclusion, the present study indicates that the induction of CYP2E1 transcription by IL-4 is mediated through two independent parallel pathways, involving JAK-STAT6 and IRS1/2 and NFATc1.
3: Journal of chemotherapy (Florence, Italy), 2010 Jun, 22(3)
Anti-IL-2 Anti-IL-4 Monoclonal Antibodies Do Not Synergize in the Suppression of Mouse Renal Cancer.
[Abstract]BACKGROUND AND OBJECTIVES: Control of the intracellular Mycobacterium tuberculosis (Mtb), mainly requires an appropriate ratio of Th1/Th2 cytokines to induce autophagy, a physiologically, and immunologically regulated process that has recently been highlighted as an innate defense mechanism against intracellular pathogens. Current vaccines/adjuvants induce both protective Th1 autophagy-promoting cytokines, such as IFN-gamma, and immunosuppressive Th2 autophagy-restraining cytokines, such as IL-4 and IL-13. TB infection itself is also characterized by relatively high levels of Th2 cytokines, which down-regulate Th1 responses and subsequently subvert adequate protective immunity, and a low ratio of IFN-gamma/IL-4. Therefore, there is a need for a safe and non-toxic vaccine/adjuvant that will induce Th1 autophagy-promoting cytokine (IFN-gamma) secretion and suppress the pre-existing subversive Th2 autophagy-restraining cytokines (IL-4 and IL-13). As lactic acid bacteria (LAB) belonging to the natural intestinal microflora and their components have been shown to shift immune responses against other antigens from Th2-type cytokines toward Th1-type cytokines like IFN-gamma, we investigated whether LAB can improve the polarization of Th1/Th2 cytokines and autophagic ability of mononuclear phagocytes in response to Mtb antigen. METHODS: Peripheral blood mononuclear cells (PBMCs), which are a part of the mononuclear phagocyte system and source of crucial macrophage activators in the in vivo situation, and human monocyte-derived macrophages (HMDMs) were treated with Mtb antigen in the presence or absence of two strains of LAB, L. rhammosus GG (LGG) and Bifidobacterium bifidum MF 20/5 (B.b). PBMCs cell culture supernatants were analyzed for the production of the autophagy-promoting factors IFN-gamma, and nitric oxide (NO) and the autophagy-restraining cytokines IL-4 and IL-13, using ELISA and Griess assays to detect the production of cytokines and NO, respectively. In HMDMs, expression of microtubule-associated protein 1 light chain 3 (LC3-I), membrane-associated (LC3-II) forms of LC3 protein and Beclin-1, as hallmarks of autophagy, were assessed using Western blot to detect the autophagy markers. The secreted interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin (IL)-12 and transformig growth factor-beta (TGF-beta), and chemokine (C-C motif) ligand 18 (CCL18) from HMDMs were determined by ELISA. Also, reverse transcription polymerase chain reaction (RT-PCR) analysis was used to assess the mRNA expressions of CCL18 in HMDMs. RESULTS: Treatment of PBMCs with either Mtb antigen or with LAB significantly increased the IFN-gamma and NO production. Combination of Mtb antigen and LAB led to synergistic increase in IFN-gamma, and an additive increase in NO. Treatment with Mtb antigen alone significantly increased the IL-4 and IL-13 production. LAB significantly decreased IL-4 and IL-13 secretion in both unstimulated and Mtb antigen-stimulated PBMCs. The IFN-gamma/IL-4+IL-13 ratio was enhanced, indicating Th1/Th2 polarization. Treatment of macrophages with combined use of Mtb antigen and LAB led to an additive increase in Beclin-1, LC3-II expression, as well as in synergistic increase in IL-12 production. Treatment of macrophages with combined use of Mtb antigen and LAB led to a decrease in IL-6, IL-10, and CCL18 secretion. LAB inhibited the secretion of TGF-beta by Mtb-stimulated macrophages, however not significantly. Treatment of macrophages with combined use of Mtb antigen and LAB led to a decrease in CCL18 mRNA expression. CONCLUSION: Our study implies that LAB may reinforce the response of the mononuclear phagocytes to Mtb antigen by inducing production of the autophagy-promoting factors IFN-gamma and NO, while decreasing the Th2 autophagy-restraining cytokines IL-4 and IL-13. Hence, combination of Mtb antigen and LAB may perhaps be safer in more efficacious TB vaccine formulation.
4: Journal of immunology (Baltimore, Md. : 1950), 2010 Jun 18, 34(1)
IFN-{gamma} Inhibits IL-4-Induced Type 2 Cytokine Expression by CD8 T Cells In Vivo and Modulates the Anti-Tumor Response.
[Abstract]Activation of naive CD8 T cells in vitro in the presence of IL-4 induces type 2 cytokine expression, loss of CD8 expression, and reduced cytolytic potential. This represents a major shift from the canonical phenotype of effector CD8 T cells. It has not been established, however, whether IL-4 can induce comprehensive type 2 cytokine expression by CD8 T cells in vivo, nor whether the effects of IL-4 on type 2 cytokine production by CD8 T cells can be inhibited by IFN-gamma. Furthermore, disparate results have been reported regarding the anti-tumor ability of type 2 polarized effector CD8 T cells, and the effects of IFN-gamma in this respect remain unknown. To address these questions, wild-type or IFN-gamma-deficient OVA-specific CD8(+) T cells were activated in RAG-2(-/- )gammac(-/-) recipients with control or IL-4-expressing OVA(+) tumor cells, and then transferred to secondary recipients for tumor challenge. Tumor-derived IL-4 induced the expression of type 2 cytokines and the transcription factor GATA-3 by responding CD8 T cells while reducing their CD8 coreceptor expression and ability to eliminate a secondary tumor challenge. Each of these effects of IL-4 was exaggerated in IFN-gamma-deficient, compared with wild-type, CD8 T cells. The results demonstrate that endogenous IFN-gamma counteracts the induction of type 2 cytokines and the downregulation of both CD8 coreceptor levels and the anti-tumor response in CD8 T cells exposed to IL-4 during activation in vivo. These findings may explain the anomalies in the reported functional phenotype of type 2 polarized CD8 T cells.
5: The Journal of experimental medicine, 2010 May 3, 47(10)
Regulation of learning and memory by meningeal immunity: a key role for IL-4.
[Abstract]Proinflammatory cytokines have been shown to impair cognition; consequently, immune activity in the central nervous system was considered detrimental to cognitive function. Unexpectedly, however, T cells were recently shown to support learning and memory, though the underlying mechanism was unclear. We show that one of the steps in the cascade of T cell-based support of learning and memory takes place in the meningeal spaces. Performance of cognitive tasks led to accumulation of IL-4-producing T cells in the meninges. Depletion of T cells from meningeal spaces skewed meningeal myeloid cells toward a proinflammatory phenotype. T cell-derived IL-4 was critical, as IL-4(-/-) mice exhibited a skewed proinflammatory meningeal myeloid cell phenotype and cognitive deficits. Transplantation of IL-4(-/-) bone marrow into irradiated wild-type recipients also resulted in cognitive impairment and proinflammatory skew. Moreover, adoptive transfer of T cells from wild-type into IL-4(-/-) mice reversed cognitive impairment and attenuated the proinflammatory character of meningeal myeloid cells. Our results point to a critical role for T cell-derived IL-4 in the regulation of cognitive function through meningeal myeloid cell phenotype and brain-derived neurotrophic factor expression. These findings might lead to the development of new immune-based therapies for cognitive impairment associated with immune decline.
6: Medical microbiology and immunology, 2010 Apr 14, 184(8)
CD28 and IL-4: two heavyweights controlling the balance between immunity and inflammation.
[Abstract]The costimulatory receptor CD28 and IL-4Ralpha-containing cytokine receptors play key roles in controlling the size and quality of pathogen-specific immune responses. Thus, CD28-mediated costimulation is needed for effective primary T-cell expansion and for the generation and activation of regulatory T-cells (Treg cells), which protect from immunopathology. Similarly, IL-4Ralpha signals are required for alternative activation of macrophages, which counteract inflammation by type 1 responses. Furthermore, immune modulation by CD28 and IL-4 is interconnected through the promotion of IL-4 producing T-helper 2 cells by CD28 signals. Using conditionally IL-4Ralpha and CD28 deleting mice, as well as monoclonal antibodies, which block or stimulate CD28, or mAb that deplete Treg cells, we have studied the roles of CD28 and IL-4Ralpha in experimental mouse models of virus (influenza), intracellular bacteria (L. monocytogenes, M. tuberculosis), and parasite infections (T. congolense, L. major). We observed that in some, but not all settings, Treg cells and type 2 immune deviation, including activation of alternative macrophages can be manipulated to protect the host either from infection or from immunopathology with an overall beneficial outcome. Furthermore, we provide direct evidence that secondary CD8 T-cell responses to i.c. bacteria are dependent on CD28-mediated costimulation.
7: Journal of the European Academy of Dermatology and Venereology : JEADV, 2010 Apr 8, 184(8)
Treatment of eosinophilic pustular folliculitis with ciclosporin: suppression of mRNA expression of IL-4 and IL-13.
[Abstract]The costimulatory receptor CD28 and IL-4Ralpha-containing cytokine receptors play key roles in controlling the size and quality of pathogen-specific immune responses. Thus, CD28-mediated costimulation is needed for effective primary T-cell expansion and for the generation and activation of regulatory T-cells (Treg cells), which protect from immunopathology. Similarly, IL-4Ralpha signals are required for alternative activation of macrophages, which counteract inflammation by type 1 responses. Furthermore, immune modulation by CD28 and IL-4 is interconnected through the promotion of IL-4 producing T-helper 2 cells by CD28 signals. Using conditionally IL-4Ralpha and CD28 deleting mice, as well as monoclonal antibodies, which block or stimulate CD28, or mAb that deplete Treg cells, we have studied the roles of CD28 and IL-4Ralpha in experimental mouse models of virus (influenza), intracellular bacteria (L. monocytogenes, M. tuberculosis), and parasite infections (T. congolense, L. major). We observed that in some, but not all settings, Treg cells and type 2 immune deviation, including activation of alternative macrophages can be manipulated to protect the host either from infection or from immunopathology with an overall beneficial outcome. Furthermore, we provide direct evidence that secondary CD8 T-cell responses to i.c. bacteria are dependent on CD28-mediated costimulation.
8: Molecular and cellular biochemistry, 2010 Apr 4, 184(8)
VEGF and IL-4 gene variability and its association with the risk of coronary heart disease in north Indian population.
[Abstract]Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor that has been shown to play a significant role in neovascularization during inflammation in atherosclerotic plaques, formation of collateral vessels to an area of ischemic myocardium and neovascularization at the edges of a myocardial infarction during its repair. Interleukin-4 (IL-4) has important role in immune cell chemotaxis, formation of endothelial cell adhesion molecules and has numerous anti-inflammatory effects which prevent the complications of atherosclerosis, the primary cause of coronary heart disease (CHD). In this study, we have analyzed the effect of 1154 A/G polymorphism of VEGF and 70 bp VNTR polymorphism of intron 3 in IL-4 genes in coronary heart disease (CHD) patients (n = 300) and their age matched controls (n = 300). To analyze polymorphic alleles, ARMS-PCR and RFLP techniques were used. Multiple logistic regression analysis was carried out with statistical software. GG genotype was associated with a decreased risk of development of CHD (OR 0.22, 95% CI 0.12-0.38, P < 0.001). However, A allele showed an increased risk whereas G allele decreased the risk of CHD with diabetes mellitus, hypertension, chronic mental stress and positive familial history of myocardial infarction (MI)/CHD. GG genotype was found to have protective effect with alcohol intake (OR 0.34, 95% CI 0.14-0.82, P < 0.01) and central obesity (OR 0.15, 95% CI 0.04-0.56, P < 0.001). GG genotype of VEGF has also shown significant association with IL-4 (P2P2 and P1P2) genotypes.
9: Journal of immunology (Baltimore, Md. : 1950), 2010 Mar 19,
IL-4 and TGF-{beta}1 Counterbalance One Another while Regulating Mast Cell Homeostasis.
[Abstract]Mast cell responses can be altered by cytokines, including those secreted by Th2 and regulatory T cells (Treg). Given the important role of mast cells in Th2-mediated inflammation and recent demonstrations of Treg-mast cell interactions, we examined the ability of IL-4 and TGF-beta1 to regulate mast cell homeostasis. Using in vitro and in vivo studies of mouse and human mast cells, we demonstrate that IL-4 suppresses TGF-beta1 receptor expression and signaling, and vice versa. In vitro studies demonstrated that IL-4 and TGF-beta1 had balancing effects on mast cell survival, migration, and FcepsilonRI expression, with each cytokine cancelling the effects of the other. However, in vivo analysis of peritoneal inflammation during Nippostrongylus brasiliensis infection in mice revealed a dominant suppressive function for TGF-beta1. These data support the existence of a cytokine network involving the Th2 cytokine IL-4 and the Treg cytokine TGF-beta1 that can regulate mast cell homeostasis. Dysregulation of this balance may impact allergic disease and be amenable to targeted therapy.
10: Journal of immunology (Baltimore, Md. : 1950), 2010 Feb 10, 30(3)
IL-4 Regulates Skin Homeostasis and the Predisposition toward Allergic Skin Inflammation.
[Abstract]IL-4 promotes the development of Th2 cells and allergic inflammation. In atopic dermatitis lesions, IL-4 decreases the expression of multiple genes associated with innate defense, including genes in the epidermal differentiation complex (EDC) that regulate epidermal barrier function. However, it is not clear whether IL-4 also contributes to homeostatic control of EDC genes. In this report, we demonstrate that expression of EDC genes and barrier function is increased in the absence of endogenous IL-4. Mice that express a constitutively active Stat6 (Stat6VT) are prone to the development of allergic skin inflammation and have decreased expression of EDC genes. IL-4 deficiency protects Stat6VT transgenic mice from the development of allergic skin inflammation and decreased recovery time in barrier function following skin irritation, with a concomitant increase in EDC gene expression. These data suggest that IL-4 plays an important role in regulating epidermal homeostasis and innate barrier function.
11: Journal of natural products, 2010 Jan 27, 37(1)
Dammarane-Type Glycosides from Gynostemma pentaphyllum and Their Effects on IL-4-Induced Eotaxin Expression in Human Bronchial Epithelial Cells.
[Abstract]Two new dammarane-type glycosides, 2alpha,3beta,12beta,20S-tetrahydroxydammar-24-ene-3-O-[beta-d-glucopyranosyl(1-->4)-beta-d-glucopyranosyl]-20-O-[beta-d-xylopyranosyl-(1-->6)-beta-d-glucopyranoside] (1) and 2alpha,3beta,12beta,20S-tetrahydroxydammar-24-ene-3-O-beta-d-glucopyranosyl-20-O-[beta-d-6-O-acetylglucopyranosyl-(1-->2)-beta-d-glucopyranoside] (2), were isolated from a MeOH extract of the leaves of Gynostemma pentaphyllum. Their structures were elucidated by 1D and 2D NMR spectroscopic interpretation as well as by chemical studies. The isolated compounds showed potential inhibitory effects on eotaxin expression in BEAS-2B bronchial epithelial cells.
12: Platelets, 2010 Jan 25, 37(1)
The expression of IFN-gamma, IL-4, Foxp3 and perforin genes are not correlated with DNA methylation status in patients with immune thrombocytopenic purpura.
[Abstract]We investigated the relationship between the expression of IFN-gamma, IL-4, Foxp3 and perforin gene and the methylation status of their promoters in immune thrombocytopenic purpura (ITP) patients. Gene expression and DNA methylation were determined by quantitative PCR and bisulfite genomic sequencing, respectively. The expression of IFN-gamma was higher, while the expression of IL-4 was notably lower in ITP patients when compared with the controls. Most importantly, the Th1/Th2 (IFN-gamma/IL-4) was remarkably higher in ITP patients, showing that the ITP patients were mainly in the Th1 polarization response. Although the methylation rate of CpGs located at -409 of perforin was higher (p = 0.0376) and that of IFN-gamma were relatively higher (p = 0.0582) in ITP, we did not find the negative correlation between the expression of those genes and the methylation of their promoters.
13: Environmental toxicology, 2010 Jan 15, 37(1)
Allergy-related cytokines (IL-4 and TNF-alpha) are induced by Di(2-ethylhexyl) phthalate and attenuated by plant-originated glycoprotein (75 kDa) in HMC-1 cells.
[Abstract]Phthalate esters as plasticizers have been widespread in the environment and may be associated with development of allergic diseases such as asthma and atopic dermatitis. In this study, we demonstrated that the CTB glycoprotein attenuates allergic reactions caused by di(2-ethylhexyl) phthalate (DEHP) in human mast cells (HMC-1). This experiment evaluated degranulation of histamine and beta-hexosaminidase as well as activities of protein kinase C (PKC), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), activator protein (AP)-1 and interleukin (IL)-4 and tumor necrosis factor (TNF)-alpha using immunoblotting and reverse transcription-polymerase chain reaction (RT-PCR). Our results revealed that the CTB glycoprotein in the presence of DEHP inhibits degranulation of mast cell, translocation of PKC from cytosol to membrane, and phosphorylation of SAPK/JNK in HMC -1 cells. We also found that the CTB glycoprotein (100 mug mL(-1)) has suppressive effects on transcriptional activation of AP-1, and on the expression of IL-4 and TNF-alpha in DEHP-treated HMC-1 cells. We suggest that the CTB glycoprotein inhibits degranulation of mast cells and expressions of cytokines in HMC-1 cells. (c) 2010 Wiley Periodicals, Inc. Environ Toxicol, 2010.
14: Genes & development, 2010 Jan 15, 37(1)
IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion.
[Abstract]Innate immune cells can constitute a substantial proportion of the cells within the tumor microenvironment and have been associated with tumor malignancy in patients and animal models of cancer; however, the mechanisms by which they modulate cancer progression are incompletely understood. Here, we show that high levels of cathepsin protease activity are induced in the majority of macrophages in the microenvironment of pancreatic islet cancers, mammary tumors, and lung metastases during malignant progression. We further show that tumor-associated macrophage (TAM)-supplied cathepsins B and S are critical for promoting pancreatic tumor growth, angiogenesis, and invasion in vivo, and markedly enhance the invasiveness of cancer cells in culture. Finally, we demonstrate that interleukin-4 (IL-4) is responsible for inducing cathepsin activity in macrophages in vitro and in vivo. Together, these data establish IL-4 as an important regulator, and cathepsin proteases as critical mediators, of the cancer-promoting functions of TAMs.
15: Proceedings of the National Academy of Sciences of the United States of America, 2010 Jan 12, 107(2)
IL-4-induced transcription factor NFIL3/E4BP4 controls IgE class switching.
[Abstract]IL-4 signaling promotes IgE class switching through STAT6 activation and the induction of Ig germ-line epsilon (GLepsilon) transcription. Previously, we and others identified a transcription factor, Nfil3, as a gene induced by IL-4 stimulation in B cells. However, the precise roles of nuclear factor, IL-3-regulated (NFIL3) in IL-4 signaling are unknown. Here, we report that NFIL3 is important for IgE class switching. NFIL3-deficient mice show impaired IgE class switching, and this defect is B-cell intrinsic. The induction of GLepsilon transcripts after LPS and IL-4 stimulation is significantly reduced in NFIL3-deficient B cells. Expression of NFIL3 in NFIL3-deficient B cells restores the impairment of IgE production, and overexpression of NFIL3 in the presence of cycloheximide induces GLepsilon transcripts. Moreover, NFIL3 binds to Iepsilon promoter in vivo. Together, these results identify NFIL3 as a key regulator of IL-4-induced GLepsilon transcription in response to IL-4 and subsequent IgE class switching.
16: Bioscience, biotechnology, and biochemistry, 2009 Nov 7, 31(12)
Transepithelial Transport of Macromolecular Substances in IL-4 Treated Human Intestinal T84 Cell Monolayers.
[Abstract]The effect of interleukin-4 (IL-4), a cytokine associated with allergy and inflammation, on the permeability of the intestinal epithelium was investigated. IL-4 reduced transepithelial electrical resistance (TER) and increased permeation to horseradish peroxidase (HRP) and Lucifer Yellow (LY) of human intestinal T84 cell monolayers. The increased permeation due to IL-4 treatment was also observed at 4 degrees C. The permeability of T84 cell monolayers to beta-lactogulobulin (beta-Lg), ovalbumin (OVA), and fluorescein isothiocyanate (FITC)-dextran of various molecular sizes was also high in the IL-4-treated cell monolayers. Sodium azide (NaN(3)), which inhibits ATP synthesis of the cells, did not inhibit the increases in these substances. Even 150 KDa FITC-dextran significantly permeated the T84 cells when the monolayers were treated with IL-4. These results suggest that fairly large molecules are able to permeate intestinal epithelial monolayers via the energy-independent paracellular pathway when the monolayers are exposed to excessive IL-4.
17: FEBS letters, 2009 Nov 5, 31(12)
USP14 stabilizes calcineurin and regulates NFAT/AP-1 dependent IL-4 transcription as a novel calcineurin-binding protein.
[Abstract]Deubiquitination plays a crucial role in selectively regulating protein degradation by the proteasome. In this study, human Usp14, a ubiquitous deubiquitinating enzyme, was found to interact with the N-terminus of calcineurin by co-immunoprecipitation. A GST pull-down assay demonstrated that the calcineurin-binding domain is located at the C-terminus (340-494aa). We have also revealed that Usp14 co-localizes with calcineurin in the cytosol and it upregulates NFAT/AP-1 dependent IL-4 transcription, while the Usp14 fragment (197-494) is unable to do so. Usp14 protects calcineurin from degradation by the proteasome in a non-catalytic fashion, while the Usp14 fragment (197-494aa) binds tightly to calcineurin and inhibits its phosphatase activity.