{"paper_id":"7c748620-d98f-475d-aff8-a8f5b2d2efc0","body_text":"Signal transducer and activator of transcription (STAT) proteins were identified as the major components of DNA-binding proteins that activate gene transcription in response to a variety of cytokines  1 . Seven different members in the STAT family (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6) have been found to regulate many physiological and pathological processes, from pathogen response to cytokine secretion  2 . The Janus kinase (JAK)-STAT pathway is a common pathway in the signaling activated by many cytokines. In JAK-STAT pathway, STAT4 was first discovered to be crucial for promoting cellular-mediated immune responses via the differentiation of Th1 cells  3 .\nSTAT4 protein contains six domains that have different functions in the JAK-STAT pathway: 1. N-terminal domain: dimerizes inactivated STATs and promotes nuclear translocation; 2. helical coiled coil: provides a carbonized hydrophilic surface and binds to regulatory factors; 3. DNA-binding domain: binds to an enhancer of the GAS family; 4. linker domain: involves in the DNA binding process; 5. Src homology (SH2) domain: binds specifically to the cytokine receptor after tyrosine phosphorylation; and 6. C-terminal transactivation domain: activates transcriptional process  4 . Additionally, with or without C-terminal transactivation, there are two spliced STAT4 transcripts, including STAT4α and STAT4β. STAT4α induces more IFN-γ production than that by STAT4β, whereas STAT4β proliferates more vigorously in response to IL12 stimulation  5 .\nIn this review, we discuss the cytokines activating STAT4 in different cells, as well as the role of STAT4 in inflammation and complex diseases, especially autoimmune diseases.\n\nAs shown in figure  1 , different combinations of STAT4 are activated by a variety of cytokines, including interleukin (IL)12, type I interferon (IFN-I), IL23, IL2, IL27, and IL35, etc.\nIL12 is produced by B cells and antigen- presenting cells and is secreted as a pro-inflammatory cytokine in the form of a heterodimer  6 . IL12 receptor (IL12R) is composed of two different subunits, including IL12Rβ1 and IL12Rβ2  7 . Upon binding to IL12R, the JAK2 and TYK2 are linked to IL12Rβ2 and IL12Rβ1, and then STAT4 is phosphorylated on tyrosine 693  8 ,  9 . Moreover, STAT4 is phosphorylated on serine 721 during activation of the p38/MKK6 signaling pathway  10 .\nThe IL12-JAK-STAT4 pathway increases IFNγ production and Th1 cell differentiation  11 ,  12 . Several other genes that require STAT4 for transcriptional activation have been identified, including activator protein 1 (AP1), IL10, ERM, IFN regulating factor (IRF)-1/4/8, IL18Rα, IL12β 2 , and Rux. STAT4 binds c-Jun, and then interacts with AP1-relevant promoter  13 . A conserved STAT4- binding element was found in the fourth intron of the IL10 gene  14 . The ETS transcription factor, EMR, is selectively expressed in Th1 cells. ERM can modulate IFNγ gene transcription with STAT4 or some STAT4 inducible factors  15 . IRF1 gene is induced via IL12-dependent transactivation of IRF1 in human natural killer (NK) and T cells  16 . Additionally, it suggests that IL12 may further strengthen innate immune responses by inducing the expression of IRF4 and IRF8 genes  17 . IL12 induces the binding of STAT4 to the IL12Rβ2 enhancer to form a positive feedback loop of IL12/STAT4 axis during T cell receptor (TCR) stimulation  18 . STAT4 binds directly to the IL18Rα locus and alters its acetylation, reducing metastatic binding and DNA methylation transiently and resulting in high expression of IL18Rα in Th1 cells  19 . The promoter regions of Runx1 and Runx3 are targets of STAT4 to promote the antiviral activity of NK cells  20 . Therefore, the IL12/STAT4 axis is vital for inflammatory cytokines secretion that participates in many diseases and anti-tumor responses. Interestingly, Gao B  et al.  found that  Stat4 \n -/-  mice are more susceptible to concanavalin A-induced T-cell hepatitis, which is inconsistent with the traditional view. Compared with wild-type mice, higher FasL expression in NK T cells in ConA-treated  Stat4 -/-  mice results in stronger cytotoxicity against hepatocytes. STAT4 may directly or indirectly inhibit the expression of FasL in NK T cells in case of the up-regulation of pro-inflammatory cytokines  21 .\nIL12 synergizes with IL18 to enhance both cytotoxicity and IFNγ production  22 - 24 . MicroRNA (miRNA)-21 inhibits the expression of IL12 by targeting its mRNA  25 . Wu  et al.  showed that miRNA-21 inhibits the expression of IL12 and STAT4 by regulating IL12 and STAT4 translation post- transcriptionally  26 . Moreover, it has recently been recognized that T follicular helper cells (Tfh cells), a different subset of Th cells, have specialized functions on promoting germinal center formation and regulating B cell function. STAT4 is required for the induction of multiple genes in the development of Tfh cells  27 . IL12Rβ1-deficient subjects do not completely lack Tfh cells, because they are able to show nearly normal levels of CXCR5 +  CD4 +  T cells during aging. Blocking the IL12/STAT4 signaling pathway might be beneficial for the treatment of these diseases by promoting the Tfh response  28 .  Stat4 \n -/-  mice with allergic lung inflammation have increased numbers of regulatory T (Treg) cells in the lung, which correlates with decreased inflammation. Stat4 may not only promote inflammation caused by T cell subsets but also limit the development of Treg cells via promoting a repressive chromatin configuration at the Foxp3 locus  29 . A recent study showed that Stat4-deficient mice have up-regulated numbers of CD4 + Foxp3 +  Tregs in mesenteric lymph nodes. Similarly, Foxp3 expression was found to be significantly increased. These findings suggest that impaired STAT4 contributes to Foxp3 +  Treg response  30 .\nIFN-I is divided into two categories: IFNα, produced by human fibroblasts, and IFNβ, produced by human leukocytes, which function as regulators of antiviral, cell proliferation inhibitory, immunity, and anti-tumor effects. Type I IFN receptor (IFNAR) contains IFNAR1 and IFNAR2. The binding of IFNα/β to IFNAR leads to the phosphorylation of STAT1 and STAT4 and activation of IFN target genes  31 . During the initial phase of a viral infection, IFNα/β mainly activate STAT4 instead of STAT1 in NK cells  32 . IFNα/β also have been reported to induce IFNγ in activated T cells and macrophages via the IFNα/β-STAT4 pathway  33 ,  34 . In response to IFNβ, STAT4 is activated in bone marrow-derived mast cells (BMMCs), which participate in immune regulation (T and B cells, APC cell activation)  34 . IL5 and IL13 induce eosinophil activation and enhance mucus production as highly inflammatory cytokine. IFNα/β inhibit expression of IL5 and IL13 in PBMCs  35 , 36 . IFNα/β induce STAT4 binding within the  IL5  promoter, repressing nascent transcription in human memory Th2 cells  37 - 39 . Moreover, Zhao  et al.  reported that STAT4 promotes retinoic acid inducible gene-1 (RIG1)-triggered type I IFN production when exposed to viral double-stranded (ds) RNA. IFNβ production in macrophages decreases after RNA virus infection in the absence of STAT4  40 . Unconventionally, during RNA virus infection, STAT4 was found unphosphorylated in the cytoplasm of macrophages. Mechanistically, STAT4 interacts with E3 ligase CHIP, which mediates the K48-linked ubiquitination of RIG1, preventing proteasomal degradation of RIG1. These findings indicate a novel role of STAT4  40 .\nWhen exposed to the pathogen-derived molecules such as Gram-positive/negative bacterial and viral products, IL23 is produced by monocytes, activated DC, and macrophages  41 - 43 . IL23 consists of IL23p19 and IL12/IL23p40 subunits. IL23 receptor (IL23R) is composed of IL12β 1  and IL23R  44 , 45 . IL23 can exert biological effects similar to IL12 via IL23R-dependent STAT4 phosphorylation, but its effects are significantly weaker than those of IL12. Unlike IL12, which only activates STAT4-STAT4 DNA-binding complexes, IL23 induces several STAT-containing DNA-binding complexes, including STAT4-STAT4 homo-dimers and STAT3-STAT4 heterodimers  46 . Notably, IL23 is involved in chronic inflammatory by inducing the differentiation and expansion of Th17 through the IL23/STAT4 signaling pathway  47 . In addition to Th cells, memory Th cells and NK T cells also display decreased IL17 production induced by IL23  48 . The IL23/STAT4 pathway has been implicated in a variety of human autoimmune and inflammatory diseases  49 , 50 . Significantly, although IL12 and IL23 have overlapping effects in disease, it is unclear how IL23 negatively regulates IFNγ production induced by IL12  50 - 51 .\nIL2 is a multifunctional cytokine produced mainly by the subset of activated CD4 +  T helper cells that act on a large variety of cells, including T and B cells, NK cells, NK T cells, neutrophils, macrophages, and monocytes after antigen activation  52 . IL2 does not affect the phosphorylation of STAT4 in T lymphocytes, although it does activate STAT4 in NK cells  53 . After stimulation with IL2, NK cells that have continuous STAT4 expression exhibit hyper-responsiveness to IL12. IL2 up-regulates the expression of IL12β1 and IL12Rβ2, and contributes to enhance and maintain the expression of STAT4 in NK cells. Through over-expression of IL12R and STAT4, NK cells show increased functional responses to IL12  54 . IL2 receptor (IL2R) has been shown to be induced via STAT4 signaling  55 . In addition, IL2 plus IL18 suppress allergic inflammation through up-regulation of IL12/STAT4 signaling, increasing IFNγ produced by NK cells  56 .\nIL27 is composed of the Epstein - Barr virus induced 3 (EBI3, IL12B-associated protein) and IL30 (IL12A-related protein), mainly secreted by antigen-presenting cells. It is reported to drive rapid expansion of CD4 +  T cells  57 . IL27 receptor (IL27R) consists of the IL27R alpha (IL27Rα) subunit and gp130, which is expressed in various immune and non-immune cells. IL27 signaling induces phosphorylation of STAT4 through TCCR/WSX-1  58 . Additionally, IL27 induces the expression of IL12Rβ2 in CD4 +  T cells by developing Th1 cells via inducing T-bet. Therefore, IL27 can establish IL12 responsiveness to STAT4 phosphorylation, contributing to the differentiation of naïve Th cells into Th1 cells during T cell immune response caused by antigen-presenting cells  in vivo \n 59 .\nIL35 is an immunosuppressive cytokine produced by Treg cells and plays an important role in many disease models. IL35 receptor (IL35R) consists of the IL12Rβ2 and gp130 domains. Naive T cells are converted into regulatory T cells (iTr35 cells) via IL35R signaling with STAT1-STAT4 heterodimer  60 . Phosphorylated STAT1 and STAT4 expand the number of Tregs in the spleen after stimulation by IL35  61 . IL35 plays critical roles in the pathogenesis of concanavalin A-induced fulminant hepatitis, reducing the FASL expression in liver mononuclear cells through the STAT1/STAT4 pathway  62 . In addition to affecting inflammation, IL35 reduces cardiac rupture, improves wound healing, and attenuates cardiac remodeling in mice with myocardial infarction by activating CX3C chemokine receptor 1 (Cx3cr1) and transforming growth factor beta-1 (Tgfβ1) in macrophages via phosphorylating Stat1 and Stat4  63 .\nIL18 belongs to the IL1 family and can be produced by a variety of tissue cells. It can induce Th1 cells to produce cytokines, enhance cytotoxic activity of NK cells, promote T cell proliferation, and synergize with IL12  64 . Unlike IL12, IL18 functions as a cofactor for Th1 cell development and produces substantial amounts of IFNγ  65 . IL12 and STAT4 affect IL18 signaling by inducing expression of MyD88 and directly affecting cellular responses to the expression of IL8 receptor (IL18R). Regulation of IFNγ may also include interactions between STAT4 and AP1 at the  IFNγ  promoter  66 . When exposed to IL12 and IL18, it enhances co-binding of the c-Jun-STAT4 complex to the AP1-relevant promoter sequence, increasing IFNγ production mediated by AP1  67 .\nIL21 is produced by Tfh cells, and regulates the functions of NK and T cells. IL21 enhances the expression of the IFNγ gene via activating STAT4 and subsequently recruiting pSTAT4 to IFNγ transcriptional sites  68 . Interestingly, IL12 also regulates the production of IL21 in CD4 +  T cells via STAT4 signaling  69 . Details of this feedback loop remain to be determined.\n\nA great deal has been discovered about STAT4 activation in response to cytokines mentioned above, whereas some studies elucidated the mechanism by which the activity of STAT4 is turned off. As shown in figure  2 , suppressor of cytokine signaling 3 (SOCS3), protein inhibitor of activated STAT (PAIS), protein tyrosine phosphatases (PTPs), and STAT-interacting LIM protein (SLIM) are believed to regulate the IL12/STAT4 signaling pathway. In addition, some miRNAs were reported to regulate STAT4 expression.\nSOCSs are released by cytokine induction, such as IL12 and IL6, and suppress the signaling of cytokines in a negative feedback loop. Phosphorylation of JAK and STAT is down-regulated in cells with high expression of SOCSs  70 . Previous studies showed that SOCS3 inhibits IL6 signaling via blocking activation of STAT3  71 . More recently, SOCS3 was shown to inhibit IL12 signaling in a negative-feedback loop. SOCS3 is recruited to IL12Rβ2, Tyr-800, the pSTAT4-recruitment site, via its SH2 domain, resulting in decreased levels of activated STAT4  72 .\nPIAS functions as a regulator of transcriptional activity in the nucleus  73 . PIASx was found in the STAT4-DNA binding complex, inhibiting STAT4- induced gene activation in T cells instead of inhibiting the combination of STAT4 and DNA. By suppressing histone deacetylase (HDAC) activity, the inhibitory activity of PIASx can be diminished. These results suggest that PIASx may be a transcriptional co-repressor of STAT4  74 .\nPTPs can remove phosphate groups from phosphorylated tyrosine in proteins. As a requirement of JAK-STAT signaling for tyrosine phosphorylation, PTPs can dephosphorylate phosphorylated proteins such as STAT4 and PTP non-receptor type 13 (PTPN13) through its PTPase domain  75 .\nSLIM is a STAT ubiquitin E3 ligase. It recruits a nuclear tyrosine phosphatase through its unique domains and then blocks tyrosine phosphorylation of STAT4  76 . IFNγ production is decreased in CD4 +  T cells in EAE mice via up-regulating SLIM by berbamine  77 .\nMiRNA functions by degrading mRNA and regulating the post-transcriptional modifications of gene expression that leads to inhibition of protein translation  78 - 79 . Some miRNAs have been found to interfere with IL12/STAT4 signaling (Table  1 ). MiRNA-146a, a key player for regulating inflammation and immune response, targets protein kinase C epsilon (PRKCε). PRKCε binds to STAT4 and then drives Th1 cell differentiation in human CD4 +  T cells. Therefore, miRNA-146a can weaken the Th1 cell immune response by targeting PRKCε  80 - 81 . MiRNA-132, miRNA-212, and miRNA-200a contribute to the down-regulation of STAT4 in NK cells via targeting the  STAT4  3′-UTR  82 . SiRNA-mediated knockdown of miRNA-155 leads to up-regulation in STAT4 expression in MyLa cells, and up-regulation of oncogenic miRNA-155 results in loss of STAT4 expression via targeting the 3'-UTR of  STAT4 \n 83 . MiR-141 have been found to target the 3′-UTR of  STAT4 , inhibiting the gastric cancer cells invasion and migration  84 . STAT4 expression is down-regulated in macrophages after overexpression of miRNA-320a, which has binding sites in the 3′-UTR of the  STAT4  gene  85 .\n\nSTAT4 is a pivotal mediator in inflammation and tumor development. Understanding the molecular mechanisms of STAT4 in immune responses and immune-mediated diseases would allow the development of novel therapeutic options for human diseases such as chronic hepatitis B (CHB), hepatocellular carcinoma (HCC), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), psoriasis, inflammatory bowel diseases (IBDs), Behçet's disease (BD), Sjögren's syndrome (SS), systemic sclerosis (SSc), primary biliary cirrhosis (PBC), and other diseases.\nCHB is the most critical risk factor for HCC and is caused by hepatitis B virus (HBV) infection  86 . In the 1990s, a complex segregation analysis provided evidence for the association of host genetics with the occurrence of HCC and suggested an interaction between HBV infection and susceptibility loci  87 . Jiang DK  et al.  showed that a single nucleotide polymorphism (SNP), rs7574865, at  STAT4  with lower mRNA levels of STAT4 is significantly associated with the HBV-related HCC risk  88 . Clark A  et al.  confirmed that rs7574865 at  STAT4  is associated with the susceptibility of CHB induced HCC  89 . In addition,  STAT4  rs7574865 was reported to be associated with CHB susceptibility as well as HBV natural clearance  90 - 92 . Recently, Jiang DK  et al.  reported that  STAT4  rs7574865 is a reliable predictor of response to IFNα therapy, a first-line therapy for CHB, in hepatitis B e antigen (HBeAg)-positive CHB patients  93 ,  94 . Hepatectomy is a main therapy for HCC, and lower STAT4 expression showed higher incidence of recurrence after this procedure. STAT4 may regulate the IFNγ production by CD8 +  T-cell infiltration of tumor tissue  95 . STAT4 was reported to be expressed at lower levels in HCC than in normal liver tissues and to be associated with serum hepatitis B surface antigen (HBsAg) level, tumor number, tumor size, and severity of HCC. STAT4 may modulate the pathological progression of HCC by inhibiting HCC cells proliferation, growth, and apoptosis, via acting as a tumor suppressor  96 .\nRA is a systemic autoimmune disorder that leads to increased risk of progressive joint degeneration, disability, and cardiovascular complications  97 . Both genetic and environmental factors have been reported to affect the pathogenesis of RA. STAT4 contributes to the differentiation and proliferation of both Th1 and Th17 cells, which are crucial effectors in chronic inflammatory disorders  98 . Increased expression of STAT4 protein in dendritic cells in the synovial membrane is associated with the rheumatoid factor in the serum, which is a risk factor for RA  99 ,  100 .\nDysregulation of STAT4 in fibroblasts also promotes the development and progression of RA  101 . IL6 is mainly secreted by fibroblasts in arthritis, regulating the inflammation process. During inflammation, fibroblasts up-regulate the expression of leukemia inhibitory factor (LIF, IL6 family cytokine) and STAT4, and the LIF/STAT4 signaling pathways contribute to IL6 transcription  102 . It is reported that Gαq in mice leads to autoimmune arthritis  103 . The level of phospho-STAT4 is higher in  Gαq -/-  CD4 +  T cells than in controls, showing that Gαq modulates T-bet and STAT4 and then regulates Th1 cell differentiation in  Gαq -/-  mice  104 . Studies indicated that inappropriate activation of STAT4 in T cells drives the inflammation in RA after tumor necrosis factor alpha (TNFα) therapy, and is unlikely to contribute to RA disease activity against a pro-inflammatory effect of STAT4  105 . Further studies on the activation of STAT4 are needed to clarify this contradiction.\nSLE affects several organs (kidney, bone, muscle, and heart) and is caused by both environmental factors and genetic susceptibility variants  106 . STAT4 deficiency is associated with deterioration of clinical nephritis with the absence of anti-dsDNA Ab  107 . STAT4-specific antisense oligonucleotide improves advanced nephritis caused by SLE  108 . Serum IFNα levels are frequently elevated in SLE patients. The SNP rs7574865 of  STAT4  affects the sensitivity of IFNα to PBMCs, resulting in greater IFNα-induced gene expression  109 .\nT1D is caused by multiple environmental and genetic factors. A variety of autoimmune antibodies that damage insulin-producing B cells in human islets can be detected in patients with T1D, leading to hyperglycemia  110 . The response of islets and β-cells to the inflammatory cytokines weakens the cell viability and function and increases the induction of apoptosis. The IL12/STAT4 axis was found to induce β-cell apoptosis  111 . Serum levels of IFNγ and IL12 are reduced in  Stat4 -/- NOD (non-obese diabetic) mice, and the development of diabetes in NOD mice is prevented with the absence of Stat4. Importantly, Stat4-deficient pancreatic islets restore insulin levels. Moreover,  Stat4 -/-  DIO (diet-induced obese) mice have increased insulin sensitivity and better glucose tolerance compared with controls  112 . In addition, Stat4 ameliorates adipose tissue inflammation that induces pancreatic β-cell dysfunction and atherosclerosis insulin resistance. Reducing the costimulatory effects of CD40 on CD8 +  T cells protects against Stat4-deficiency in a diet-induced obesity model  113 ,  114 .\nPsoriasis is characterized by the hyper- proliferation and aberrant differentiation of keratinocytes  115 . The migration of Th1 cells produces IFNγ, which leads to keratinocyte hyper-proliferation, small vessel proliferation, and inflammatory infiltration in the skin, events that play a key role in the pathogenesis of psoriasis  116 . Higher levels of pSTAT4 have been described in psoriatic T cells compared with the skin of non-psoriatic donors, which increases responses to IFNα and leads to up-regulated IFNγ production  117 .\nIBDs, including ulcerative colitis (UC) and Crohn's disease (CD), are chronic inflammatory disorders characterized by aberrant mucosal Th1 cell activation and production of cytokines promoted by IL12/ STAT4 signaling  118 . IL12 is up-regulated in active CD and UC with high amounts of IFNγ produced by lamina propria lymphocytes, and STAT4 is activated in patients with increased expression of IL12Rβ2  119 . As an alternatively spliced isoform of STAT4, STAT4β activates neutrophils present in the lamina propria by enhancing TNFα and GM-CSF secretion and promoting colitis  in vivo . Regulation of  STAT4  mRNA splicing is important in the progression of human disease  120 . Moreover, STAT4 activated by LIF inhibits Th17 accumulation and promotes repair of damaged intestinal epithelium blocking STAT3-dependent  IL17α/IL17  promoter activation  121 . Interestingly,  STAT4  variants affect DNA methylation status at position -172 of the  STAT4  gene in IBD patients, and the T allele of  STAT4  rs7574865 shows significantly higher methylation levels  122 .\nBD is a systemic immune system disease that invades many organs of the human body, including the mouth, skin, joint muscles, eyes, blood vessels, heart, lungs, and the nervous system  123 . It has been reported that  STAT4  polymorphisms confer susceptibility to BD. The risk alleles A of rs7574070 and A of rs897200 are associated with up-regulation of STAT4 along with increased expression of IL17 in patients with more serious BD, suggesting that these risk alleles contribute to BD through the Th17 pathway instead of the Th1 pathway  124 ,  125 .\nSS is an autoimmune disorder caused by lymphocytic infiltration of exocrine glands that results in dysfunction of the salivary and lacrimal glands  124 . Patients with primary SS (pSS) have an increased response of IFN-I, leading to the etiopathogenesis and clinical outcome of the disease  126 . IFN-I/STAT4 signaling pathways play a key role in autoimmune diseases  127 .Nordmark G  et al.  showed that IRF5 and STAT4 are components of the IFN-I system and emphasized the importance of this system in the etiopathogenesis of pSS  128 .\nSSc is a systemic connective-tissue disease characterized by excessive deposition of collagen in many tissues, causing fibrosis of skin, internal organs, and microvascular diseases  129 . STAT4 may play an essential role in fibrosis. Avouac J  et al . found that fibrotic skin lesions induced by subcutaneous injections of bleomycin or saline in WT mice were almost totally absent in the  Stat4 -/-  mice and had lower numbers of infiltrating leukocytes. STAT4 may increase the release of cytokines involved in fibrotic processes to regulate the activation of fibroblasts  130 . SSc includes two clinical phenotypes, limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc). Rueda  et al.  found that  STAT4  variants were associated with susceptibility to lcSSc instead of dcSSc  131 .\nPBC is characterized by a progressive T cell-predominant lymphocytic cholangitis, and positive anti-mitochondrial antibodies (AMA). Genes involved in IL12/STAT4 signaling in CD4 +  T cells confer susceptibility risks for PBC  132 . Moreover, antinuclear antibodies (ANA) are associated with more rapid progression and a poorer prognosis in patients with PBC, and variants of  STAT4  are reported to be associated with ANA  133 . Apart from IL12/Th1 signaling, bile duct cells increase IL23/Th17 signaling as expression of IL12Rβ2 and IL23R is increased in cholangiocytes in the initial phases of PBC  134 . Liaskou E  et al.  found increased sensitivity of PBC Treg cells to low doses of IL12 through the IL12-STAT4 pathway, driving their differentiation into IFN-γ secreting cells  135 .\nEndometriosis, ovarian cancer (OC), and chronic lymphocytic leukemia (CLL) B cells have also been found to be associated with STAT4 in recent years. Although there are only a few studies till present, they are important for understanding the development of these diseases.\nEndometriosis is a common gynecological disorder that is histologically similar to the endometrial and/or stromal tissue grown in the uterine cavity and can lead to pelvic pain, dysmenorrhea, and infertility  136 . IFNγ has been found to be reduced in peripheral lymphocytes in endometriosis, and its concentration in PF is decreased  137 . Zamani MR  et al.  found a significant association between  STAT4  rs7582694 and susceptibility to endometriosis  138 .\nOC is usually diagnosed at a late stage in gynecological cancers. Overexpression of STAT4 has been found in epithelial cells of OC and with poor prognosis of patients. STAT4 mediates the EMT process via cancer-stroma interactions, and promotes metastasis via cancer-associated fibroblasts induced by Wnt7a  139 .\nCLL is a B-cell neoplasm that accumulates monoclonal CD5 +  B cells  140 . P66Shc attenuates BCR-dependent survival signals and modulates Bcl-2 expression as a regulator of B-cell apoptosis. The lack of p66Shc in CLL B cells causes an imbalance toward antiapoptotic Bcl-2 family members  141 - 143 . Recently, Guo  et al.  showed that silencing or over-expression of STAT4 resulted in co-modulation of transcriptional regulator of p66Shc in B cells. STAT4 activation increases the coordination of STAT4 and p66Shc expression, enhancing B cell apoptosis. P66Shc has been shown to promote STAT4 expression in a positive feedback loop  144 .\n\nDistinct types of cytokines can activate STAT4 in multiple cells such as tumor or immune cells via the JAK-STAT pathway.  In vivo  and  in vitro  studies in recent decades have suggested that STAT4 may induce inflammation and autoimmune diseases, inhibit tumor growth or promote tumors via regulating many facets of the innate and adaptive immune responses.\nSTAT4 increases the Th1 cells differentiation, cytotoxicity and IFNγ production of immune cells. In addition, STAT4 regulates the migration and proliferation of tumor cells. As it can be activated in both tumor cells and immune cells, we suspect that STAT4 may modulate the interaction between tumor cells and host immunity. More researches need to be carried out to understand whether STAT4 affects anti-cancer immune responses and immunologic microenvironment in tumors.\nWhile STAT4 exerts functions in many tumor cells or immune cells such as T cell and NK cell, we lack insight into whether and how it regulates other kinds of cells, including Tfh cell  27 - 28 , Treg cell  29 - 30 , fibroblast  102 , mast cell  145  and endothelial precursor cell  146 . If further researches are performed, additional molecular activities of STAT4 in these cells may be discovered.\nAdditionally, as we have mentioned, SNPs in  STAT4  are associated with a variety of diseases. There have been limited researches about the molecular mechanisms by which the variants of  STAT4  affect these diseases. Further studies  in vivo  and  in vitro  should focus on how the SNPs in  STAT4  contribute to immune dysregulation and autoimmunity.\nIn summary, the cytokines activating STAT4, the responsive genes of STAT4 and the molecular mechanisms of how STAT4 is involved in human diseases require more studies to accelerate the breakthrough process, and treatment strategies for human diseases are also needed to be established based on breakthroughs regarding STAT4.","source_license":"CC-BY-4.0","license_restricted":false}