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![STAT3 is important to activate the MAD1 promoter. (A) Schematic representation of the cytoplasmic portion of the G-CSF receptor (G-CSFR). The conserved boxes 1–3 and the four tyrosine residues that are known to be phosphorylated in response to G-CSF are indicated. The signal transduction pathways that are connected to the individual tyrosine residues are given. (B) RK13 cells were cotransfected with the –184 to +248 MAD1 promoter luciferase reporter construct and expression plasmids for the indicated wild-type G-CSFR or deletion mutants. The cells were stimulated with G-CSF prior to harvesting and measuring luciferase and β-galactosidase activity. A typical experiment performed in triplicates is shown. (C and D) The experimental design was as in (B). G-CSFR mutants with the indicated changes of either individual tyrosine residues or combination of tyrosines were analyzed. (E) The transfections were performed as in panel B with the additional co-expression of different STAT factors as indicated. A typical experiment performed in duplicates is shown. (F) The experiment was done as in panel B. A dominant negative version of STAT3 [STAT3(Y705F)] was co-expressed as indicated.](profile/Juliane-Luescher-Firzlaff/publication/5647357/figure/fig5/AS:202713993355275@1425342190400/STAT3-is-important-to-activate-the-MAD1-promoter-A-Schematic-representation-of-the.png)
STAT3 is important to activate the MAD1 promoter. (A) Schematic representation of the cytoplasmic portion of the G-CSF receptor (G-CSFR). The conserved boxes 1–3 and the four tyrosine residues that are known to be phosphorylated in response to G-CSF are indicated. The signal transduction pathways that are connected to the individual tyrosine residues are given. (B) RK13 cells were cotransfected with the –184 to +248 MAD1 promoter luciferase reporter construct and expression plasmids for the indicated wild-type G-CSFR or deletion mutants. The cells were stimulated with G-CSF prior to harvesting and measuring luciferase and β-galactosidase activity. A typical experiment performed in triplicates is shown. (C and D) The experimental design was as in (B). G-CSFR mutants with the indicated changes of either individual tyrosine residues or combination of tyrosines were analyzed. (E) The transfections were performed as in panel B with the additional co-expression of different STAT factors as indicated. A typical experiment performed in duplicates is shown. (F) The experiment was done as in panel B. A dominant negative version of STAT3 [STAT3(Y705F)] was co-expressed as indicated.
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MAD family proteins are transcriptional repressors that antagonize the functions of MYC oncoproteins. In particular, MAD1
has been demonstrated to interfere with MYC-induced proliferation, transformation and apoptosis. The MAD1 gene is expressed in distinct patterns, mainly associated with differentiation and quiescence. We observed that MAD1 is di...
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... signal transduction pathways that mediate MAD1 activation G-CSFR signaling is mediated by proteins recruited to the region proximal to the transmembrane domain and, upon phosphorylation, through four tyrosine residues Nucleic Acids Research, 2008, Vol. 36, No. 5 1523 (Y704, Y729, Y744 and Y764, summarized in Figure 5A) (35,36). To address the role of these elements for signaling to the MAD1 promoter, we used receptor deletion mutants. ...Context 2
... address the role of these elements for signaling to the MAD1 promoter, we used receptor deletion mutants. Loss of the distal region of the cytoplasmic portion of the G-CSFR in three different deletion mutants (52), including all four tyrosine residues, completely abolished stimulation of the -184 to +248 MAD1 promoter construct ( Figure 5B). This suggested that the Tyr residues might be critical to mediate the signaling to the MAD1 promoter. ...Context 3
... we used G-CSFR mutants, in which only a single tyrosine residue was maintained while the others were mutated to phenylala- nine (41). We observed that when either only Y704 or only Y744 was present (lacking the SOCS3-binding sites that mediates repression), stimulation was more pronounced than with the wild-type (wt) G-CSFR ( Figure 5C). .4 ...Context 4
... the role of Y704, the major STAT3- binding site, was further substantiated. Mutation of this tyrosine in G-CSFR(Y704F) was sufficient to significantly reduce activation of the MAD1 promoter construct ( Figure 5D). In contrast, mutation of Y744 had little consequence ( Figure 5D), consistent with the finding that through this tyrosine STAT3 can be activated but to a lesser degree than through Y704 (41). ...Context 5
... of this tyrosine in G-CSFR(Y704F) was sufficient to significantly reduce activation of the MAD1 promoter construct ( Figure 5D). In contrast, mutation of Y744 had little consequence ( Figure 5D), consistent with the finding that through this tyrosine STAT3 can be activated but to a lesser degree than through Y704 (41). These findings suggest that efficient activation of STAT3 is important to stimulate the MAD1 promoter. ...Context 6
... findings suggest that efficient activation of STAT3 is important to stimulate the MAD1 promoter. A receptor mutant with only Y764 showed comparable activity to wt G-CSFR ( Figure 5C). However, loss of this tyrosine in G-CSFR(Y764F) was not sufficient to reduce the stimulatory effect on the MAD1 promoter ( Figure 5D), indicating that most likely alternative mechanisms exist to activate the MAPK and/or PI3K/AKT signal transduction pathways. ...Context 7
... receptor mutant with only Y764 showed comparable activity to wt G-CSFR ( Figure 5C). However, loss of this tyrosine in G-CSFR(Y764F) was not sufficient to reduce the stimulatory effect on the MAD1 promoter ( Figure 5D), indicating that most likely alternative mechanisms exist to activate the MAPK and/or PI3K/AKT signal transduction pathways. In contrast to the other Tyr residues, when only Y729 was present substantially reduced MAD1 promoter stimulation was observed (Figure 5C), while G-CSFR(Y729F) was sub- stantially more active ( Figure 5D). ...Context 8
... loss of this tyrosine in G-CSFR(Y764F) was not sufficient to reduce the stimulatory effect on the MAD1 promoter ( Figure 5D), indicating that most likely alternative mechanisms exist to activate the MAPK and/or PI3K/AKT signal transduction pathways. In contrast to the other Tyr residues, when only Y729 was present substantially reduced MAD1 promoter stimulation was observed (Figure 5C), while G-CSFR(Y729F) was sub- stantially more active ( Figure 5D). Thus it appears that Y729, which recruits the suppressor of cytokine signaling (SOCS) 3, is mainly involved in signal repression, as suggested before, and demonstrated here by the strong effects on MAD1 promoter activity. ...Context 9
... loss of this tyrosine in G-CSFR(Y764F) was not sufficient to reduce the stimulatory effect on the MAD1 promoter ( Figure 5D), indicating that most likely alternative mechanisms exist to activate the MAPK and/or PI3K/AKT signal transduction pathways. In contrast to the other Tyr residues, when only Y729 was present substantially reduced MAD1 promoter stimulation was observed (Figure 5C), while G-CSFR(Y729F) was sub- stantially more active ( Figure 5D). Thus it appears that Y729, which recruits the suppressor of cytokine signaling (SOCS) 3, is mainly involved in signal repression, as suggested before, and demonstrated here by the strong effects on MAD1 promoter activity. ...Context 10
... is supported by the analysis of the different G-CSFR mutants in combination with MAD1 promoter analysis. Indeed co-expression of STAT3, but not other STATs, was sufficient to enhance the G-CSF/G-CSFR response of the -184 to +248 MAD1 promoter reporter construct ( Figure 5E). Furthermore, co-expression of a dominant negative mutant of STAT3 (STAT3(Y705F)) that cannot be phosphorylated on this tyrosine was sufficient to reduce the G-CSF/G-CSFR-dependent activation of the -184/ +248-luc or of the -184/-58-mintk-luc reporter gene constructs ( Figure 5F and data not shown). ...Context 11
... co-expression of STAT3, but not other STATs, was sufficient to enhance the G-CSF/G-CSFR response of the -184 to +248 MAD1 promoter reporter construct ( Figure 5E). Furthermore, co-expression of a dominant negative mutant of STAT3 (STAT3(Y705F)) that cannot be phosphorylated on this tyrosine was sufficient to reduce the G-CSF/G-CSFR-dependent activation of the -184/ +248-luc or of the -184/-58-mintk-luc reporter gene constructs ( Figure 5F and data not shown). Similarly, the activities of G-CSFR mutants with only one Tyr residue, i.e. ...Context 12
... the activities of G-CSFR mutants with only one Tyr residue, i.e. Y704 or Y744, were sensitive to STAT3(Y705F) (Figure 5F). The G-CSFR mutant with only Y764 was weakly sensitive to STAT3(Y705F), possibly a conse- quence of the reported tyrosine-independent activation of STAT3 by G-CSFR [41,53]. ...Similar publications
Severe congenital neutropenia (CN) is characterized by a maturation arrest of myelopoiesis at the promyelocyte stage. Treatment with pharmacological doses of recombinant human granulocyte colony-stimulating factor (rh-G-CSF) stimulates neutrophil production and decreases the risk of major infectious complications. However, approximately 15% of CN p...
Using a human melanoma/Scid xenograft model with the C8161, M24-met, LD-1 and other human melanoma lines to investigate spontaneous metastasis, we made the observation of marked splenomegaly (up to five times normal weight and size) in only those xenografts exhibiting high degrees of spontaneous metastasis. Evaluation of this revealed the cause to...
G-CSF is a potent hematopoietic factor that enhances survival and drives differentiation of myeloid lineage cells, resulting in the generation of neutrophilic granulocytes. Here, we show that G-CSF passes the intact blood-brain barrier and reduces infarct volume in 2 different rat models of acute stroke. G-CSF displays strong anti-apoptotic activit...
Granulocyte-colony-stimulating factor (G-CSF) stimulates the proliferation and differentiation of cells of the neutrophil lineage by interaction with a specific receptor. Early signal transduction events following G-CSF receptor activation were studied. We detected tyrosine phosphorylation of both the G-CSF receptor and the protein tyrosine kinase...
Since radioiodination of human granulocyte colony-stimulating factor (G-CSF) is difficult, we synthesized a mutein of human G-CSF that retains full biological activity and receptor-binding capacity for at least 2 weeks after radioiodination. Receptors for human G-CSF were characterized in the plasma membrane fraction from the human term placenta (h...
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... EVA1A-AS and EVA1A proximal promoter regions contain 9x and 1x E-BOX (CANNTG), respectively (Fig. 5E). To determine whether these putative promoters are indeed activated by Myc, both proximal promoter regions were fused to the luciferase gene and the reporter assay was performed in the presence or absence of Myc 10 . In the presence of Myc, EVA1A-AS and EVA1A putative promoters were activated 14-and 3.3 -fold in the absence of Myc, respectively (Fig. 5E). ...
The Myc gene has been implicated in the pathogenesis of most types of human cancerous tumors. Myc/Max activates large numbers of pro-tumor genes; however it also induces anti-proliferation genes. When anti-proliferation genes are activated by Myc, cancer cells can only survive if they are downregulated. Hepatocellular carcinoma (HCC) specific intronic long noncoding antisense (lnc-AS) RNA, the EVA1A-AS gene, is located within the second intron (I2) of the EVA1A gene (EVA-1 homolog A) that encodes an anti-proliferation factor. Indeed, EVA1A, but not EVA1A-AS, is expressed in normal liver. Depletion of EVA1A-AS suppressed cell proliferation of HepG2 cells by upregulation of EVA1A. Overexpression of EVA1A caused cell death at the G2/M phase via microtubule catastrophe. Furthermore, suppressed EVA1A expression levels are negatively correlated with differentiation grade in 365 primary HCCs, while EVA1A-AS expression levels are positively correlated with patient survival. Notably, both EVA1A and EVA1A-AS were activated by the Myc/Max complex. Eva1A-AS is transcribed in the opposite direction near the 3′splice site of EVA1A I2. The second intron did not splice out in a U2 dependent manner and EVA1A mRNA is not exported. Thus, the Myc/Max dependent anti-proliferating gene, EVA1A, is controlled by Myc/Max dependent anti-sense noncoding RNA for HCC survival.
... This result indicates that other signal pathways could be involved. Recently, Mad1 promoter sequences have been cloned [54]. This study provides a first analysis of the Mad1 promoter and suggests that STAT3 functions as a C/EBP cofactor in the regulation of the Mad1 gene. ...
... Furthermore, we find that DAF-16 activity regulates Myc family expression. This is reminiscent of the reported function of mammalian MAD1, which is upregulated at the transcriptional level by several different signaling pathways, including activated PI3K/Akt downstream of the granulocytecolony stimulating factor receptor (G-CSFR) [76]. This contrasts with findings that identified mdl-1 as an upregulated DAF-16 target gene by microarray analysis [13,77]. ...
The Myc family of transcription factors regulates a variety of biological processes, including the cell cycle, growth, proliferation, metabolism, and apoptosis. In Caenorhabditis elegans, the "Myc interaction network" consists of two opposing heterodimeric complexes with antagonistic functions in transcriptional control: the Myc-Mondo:Mlx transcriptional activation complex and the Mad:Max transcriptional repression complex. In C. elegans, Mondo, Mlx, Mad, and Max are encoded by mml-1, mxl-2, mdl-1, and mxl-1, respectively. Here we show a similar antagonistic role for the C. elegans Myc-Mondo and Mad complexes in longevity control. Loss of mml-1 or mxl-2 shortens C. elegans lifespan. In contrast, loss of mdl-1 or mxl-1 increases longevity, dependent upon MML-1:MXL-2. The MML-1:MXL-2 and MDL-1:MXL-1 complexes function in both the insulin signaling and dietary restriction pathways. Furthermore, decreased insulin-like/IGF-1 signaling (ILS) or conditions of dietary restriction increase the accumulation of MML-1, consistent with the notion that the Myc family members function as sensors of metabolic status. Additionally, we find that Myc family members are regulated by distinct mechanisms, which would allow for integrated control of gene expression from diverse signals of metabolic status. We compared putative target genes based on ChIP-sequencing data in the modENCODE project and found significant overlap in genomic DNA binding between the major effectors of ILS (DAF-16/FoxO), DR (PHA-4/FoxA), and Myc family (MDL-1/Mad/Mxd) at common target genes, which suggests that diverse signals of metabolic status converge on overlapping transcriptional programs that influence aging. Consistent with this, there is over-enrichment at these common targets for genes that function in lifespan, stress response, and carbohydrate metabolism. Additionally, we find that Myc family members are also involved in stress response and the maintenance of protein homeostasis. Collectively, these findings indicate that Myc family members integrate diverse signals of metabolic status, to coordinate overlapping metabolic and cytoprotective transcriptional programs that determine the progression of aging.
... G-CSF is made up of 4 anti-parallel α-helices (4), and the G-CSF : G-CSF-receptor (G-CSFR) complex forms a 2 : 2 stoichiometry by means of a cross-over interaction between the Ig-like domains of G-CSFR and G-CSF (5). G-CSF stimulates the JAK2/STAT3 pathway in the human promyelocyte cell line HL60 (6). Survivin is stimulated by granulocyte-macrophage (GM) CSF in CD34 + bone marrow and HL60 cells (7) and is activated by STAT3, which is induced by G-CSF, in a bladder carcinoma cell line (8). ...
Granulocyte colony-stimulating factor (G-CSF) is a cytokine secreted by stromal cells and plays a role in the differentiation of bone marrow stem cells and proliferation of neutrophils. Therefore, G-CSF is widely used to reduce the risk of serious infection in immunocompromised patients; however, its use in such patients is limited because of its non-persistent biological activity. We created an N-linked glycosylated form of this cytokine, hG-CSF (Phe140Asn), to assess its biological activity in the promyelocyte cell line HL60. Enhanced biological effects were identified by analyzing the JAK2/STAT3/survivin pathway in HL60 cells. In addition, mutant hG-CSF (Phe140Asn) was observed to have enhanced chemoattractant effects and improved differentiation efficiency in HL60 cells. These results suggest that the addition of N-linked glycosylation was successful in improving the biological activity of hG-CSF. Furthermore, the mutated product appears to be a feasible therapy for patients with neutropenia.
... Moreover MAD1 expression is directly downregulated by MYC (NH and BL, unpublished observations). In particular several differentiation inducing agents, including transforming growth factor b (TGFb), retinoic acid, and granulocyte-colony stimulating factor (G-CSF), were identified as stimulators of MAD1 expression1617181920. These findings led us to address the question how the MAD1 promoter is organized and how signals of these differentiation factors control gene expression. ...
... These findings led us to address the question how the MAD1 promoter is organized and how signals of these differentiation factors control gene expression. The MAD1 promoter contains a CpG island as part of a roughly 400 bp proximal promoter region highly conserved between humans and rodents [17]. This region is responsive to G-CSF, integrating signals transduced from the G-CSF receptor by STAT3 and by the RAS- RAF-ERK pathway. ...
... Moreover it has been found that SMAD proteins may interact with C/EBP transcription factors to control gene expression [27]. Since we have shown previously that C/EBPs control the transcription of MAD1 in response to the cytokine G-CSF in RK13 rabbit epithelial cells [17], we addressed the role of C/EBP transcription factors in human cells. Transient transfection experiments in HeLa cells demonstrated that C/EBPa and b, and to a lesser extend C/EBPε, were able to stimulate -1282 to +248 and -184 to +248 (relative to the major transcriptional start site) MAD1 promoter reporter gene constructs (Figure 2A-C). ...
The MAD1 protein, a member of the MYC/MAX/MAD network of transcriptional regulators, controls cell proliferation, differentiation and apoptosis. MAD1 functions as a transcriptional repressor, one direct target gene being the tumor suppressor PTEN. Repression of this gene is critical to mediate the anti-apoptotic function of MAD1. Under certain conditions it also antagonizes the functions of the oncoprotein MYC. Previous studies have demonstrated that MAD1 expression is controlled by different cytokines and growth factors. Moreover we have recently demonstrated that the MAD1 promoter is controlled by the cytokine granulocyte colony-stimulating factor (G-CSF) through the activation of STAT3, MAP kinases and C/EBP transcription factors.
We observed that in addition to G-CSF, the cytokine transforming growth factor β (TGFβ1) rapidly induced the expression of MAD1 mRNA and protein in promyelocytic tumor cells. Moreover we found that C/EBP and SP transcription factors cooperated in regulating the expression of MAD1. This cooperativity was dependent on the respective binding sites in the proximal promoter, with the CCAAT boxes being bound by C/EBPα/β heterodimers. Both C/EBP and SP transcription factors bound constitutively to DNA without obvious changes in response to TGFβ1. In addition SMAD3 stimulated the MAD1 reporter, cooperated with C/EBPα and was bound to the core promoter region. Thus SMAD3 appears to be a potential link between TGFβ1 signaling and C/EBP regulated promoter activity. Moreover TGFβ1 stimulated the phosphorylation of polymerase II at serine 2 and its progression into the gene body, consistent with enhanced processivity.
Our findings suggest that C/EBP and SP factors provide a platform of transcription factors near the core promoter of the MAD1 gene that participate in mediating signal transduction events emanating from different cytokine receptors. SMAD3, a target of TGFβ1 signaling, appears to be functionally relevant. We suggest that a key event induced by TGFβ1 at the MAD1 promoter is the recruitment or activation of cofactors, possibly in complex with C/EBP, SP, and SMAD3 transcriptional regulators, that control polymerase activity.
... This result indicates that other signal pathways could be involved. Recently, Mad1 promoter sequences have been cloned [54]. This study provides a first analysis of the Mad1 promoter and suggests that STAT3 functions as a C/EBP cofactor in the regulation of the Mad1 gene. ...
In human cells the length of telomeres depends on telomerase activity. This activity and the expression of the catalytic subunit of human telomerase reverse transcriptase (hTERT) is strongly up-regulated in most human cancers. hTERT expression is regulated by different transcription factors, such as c-Myc, Mad1 and Sp1. In this study, we demonstrated that 15d-PG J2 and rosiglitazone (an endogenous and synthetic peroxisome proliferators activated receptor gamma (PPARgamma) ligand, respectively) inhibited hTERT expression and telomerase activity in CaCo-2 colon cancer cells. Moreover, both ligands inhibited c-Myc protein expression and its E-box DNA binding activity. Additionally, Mad1 protein expression and its E-box DNA binding activity were strongly increased by 15d-PG J2 and, to a lesser extent, by rosiglitazone. Sp1 transcription factor expression and its GC-box DNA binding activity were not affected by both PPARgamma ligands. Results obtained by transient transfection of CaCo-2 cells with pmaxFP-Green-PRL plasmid constructs containing the functional hTERT core promoter (including one E-box and five GC-boxes) and its E-box deleted sequences, cloned upstream of the green fluorescent protein reporter gene, demonstrated that 15d-PG J2, and with minor effectiveness, rosiglitazone, strongly reduced hTERT core promoter activity. E-boxes for Myc/Mad/Max binding showed a higher activity than GC-boxes for Sp1. By using GW9662, an antagonist of PPARgamma, we demonstrated that the effects of 15d-PG J2 are completely PPARgamma independent, whereas the effects of rosiglitazone on hTERT expression seem to be partially PPARgamma independent. The regulation of hTERT expression by 15d-PG J2 and rosiglitazone, through the modulation of the Myc/Max/Mad1 network, may represent a new mechanism of action of these substances in inhibiting cell proliferation.
Cancer cells depend on transcription of telomerase reverse transcriptase (TERT). Many transcription factors affect TERT, though regulation occurs in context of a broader network. Network effects on telomerase regulation have not been investigated, though deeper understanding of TERT transcription requires a systems view. However, control over individual interactions in complex networks is not easily achievable. Mathematical modelling provides an attractive approach for analysis of complex systems and some models may prove useful in systems pharmacology approaches to drug discovery. In this report, we used transfection screening to test interactions among 14 TERT regulatory transcription factors and their respective promoters in ovarian cancer cells. The results were used to generate a network model of TERT transcription and to implement a dynamic Boolean model whose steady states were analysed. Modelled effects of signal transduction inhibitors successfully predicted TERT repression by Src-family inhibitor SU6656 and lack of repression by ERK inhibitor FR180204, results confirmed by RT-QPCR analysis of endogenous TERT expression in treated cells. Modelled effects of GSK3 inhibitor 6-bromoindirubin-3'-oxime (BIO) predicted unstable TERT repression dependent on noise and expression of JUN, corresponding with observations from a previous study. MYC expression is critical in TERT activation in the model, consistent with its well known function in endogenous TERT regulation. Loss of MYC caused complete TERT suppression in our model, substantially rescued only by co-suppression of AR. Interestingly expression was easily rescued under modelled Ets-factor gain of function, as occurs in TERT promoter mutation. RNAi targeting AR, JUN, MXD1, SP3, or TP53, showed that AR suppression does rescue endogenous TERT expression following MYC knockdown in these cells and SP3 or TP53 siRNA also cause partial recovery. The model therefore successfully predicted several aspects of TERT regulation including previously unknown mechanisms. An extrapolation suggests that a dominant stimulatory system may programme TERT for transcriptional stability.
Over the past decade, there has been much interest in the regulation of telomerase, the enzyme responsible for maintaining the integrity of chromosomal ends, and its crucial role in cellular immortalization, tumorigenesis, and the progression of cancer. Telomerase activity is characterized by the expression of the telomerase reverse transcriptase (TERT) gene, suggesting that TERT serves as the major limiting agent for telomerase activity. Recent discoveries have led to characterization of various interactants that aid in the regulation of human TERT (hTERT), including numerous transcription factors; further supporting the pivotal role that transcription plays in both the expression and repression of telomerase. Several studies have suggested that epigenetic modulation of the hTERT core promoter region may provide an additional level of regulation. Although these studies have provided essential information on the regulation of hTERT, there has been ambiguity of the role of methylation within the core promoter region and the subsequent binding of various activating and repressive agents. As a result, we found it necessary to consolidate and summarize these recent developments and elucidate these discrepancies. In this review, we focus on the co-regulation of hTERT via transcriptional regulation, the presence or absence of various activators and repressors, as well as the epigenetic pathways of DNA methylation and histone modifications.
Atopic dermatitis (AD) is an inflammatory skin disease affecting 10% to 20% of children and 1% to 3% of adults in industrialized countries. Enhanced expression of IL-31 is detected in skin samples of patients with AD, but its physiological relevance is not known.
We sought to determine the role of IL-31 in skin differentiation.
We used human 3-dimensional organotypic skin models with either primary keratinocytes or HaCaT keratinocytes with inducible IL-31 receptor α to evaluate the effect of IL-31. The consequences were studied by using histology, the expression of markers analyzed by immunofluoresence and quantitative RT-PCR, and gene expression arrays.
We observed that IL-31 interferes with keratinocyte differentiation. Gene expression analysis revealed a limited set of genes deregulated in response to IL-31, including IL20 and IL24. In HaCaT keratinocytes with inducible IL-31 receptor α, IL-31 inhibited proliferation upon induction of IL-31 receptor α by inducing cell cycle arrest. As in primary cells, IL-31-treated HaCaT cells elicited a differentiation defect in organotypic skin models, associated with reduced epidermal thickness, disturbed epidermal constitution, altered alignment of the stratum basale, and poor development of the stratum granulosum. The differentiation defect was associated with a profound repression of terminal differentiation markers, including filaggrin, an essential factor for skin barrier formation, and a reduced lipid envelope. The highly induced proinflammatory cytokines IL-20 and IL-24 were responsible for part of the effect on FLG expression and thus for terminal differentiation.
Our study suggests that IL-31 is an important regulator of keratinocyte differentiation and demonstrates a link between the presence of IL-31 in skin, as found in patients with AD, and filaggrin expression.
