Stat3 is activated by cytokines of the IL-6 family such as IL-6, IL-11, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), oncostatin M and cardiotropin I .
Stat3 is the major signal transducer downstream of gp130-like receptors .
Other extracellular signaling ligands such as IL-10 family members, epidermal growth factor (EGF), platelet derived growth factor (PDGF), hepa- tocyte growth factor (HGF), granulocyte colony- stimulating factor (G-CSF) and leptin have also known to activate Stat3.
Different tyrosine kinases (TKs) can induce Stat3 activation. Growth factors such as EGF bind to receptor tyrosine kinases (RTKs), followed by phosphorylation of Stat3 through activation of intermediary kineases of the SRC and JAK families. Cytokines such as IL-6 family members bind to gp130, a common receptor subunit, thereby JAK families and subsequent Stat3 are activated. Non-receptor TKs such as SRC and ABL can directly phophorylate Stat3 in the absence of ligand-dependent receptor signaling. In any pathway, two tyrosine phosphorylated Stat3 proteins form dimers, enter the nucleus and bind DNA to activate transcription of the target genes
Regulation of the STAT3 signal transduction pathway
Cytokine-binding induces receptor oligomerization that facilitates cross-phosphorylation and activation of receptor-associated JAK kinases.
Recruitment of STAT3 proteins to the activated receptor complex results in their activation, dimerization and translocation into the nucleus
In the nucleus they to induce the expression of cytokine-responsive genes including, SOCS3 and to a lesser extent, SOCS1. SOCS proteins inhibit or terminate JAK/STAT signals by binding to tyrosine-phosphorylated JAKs and/or cytokine receptors and targeting them for degradation.
The STAT3signal can also be attenuated by PIAS3, a member of the protein inhibitors of activated STATs (PIAS) family of proteins. PIAS3 binds selectively to activated STAT3 dimers and blocks their ability to activate gene transcription.
Regulation of the STAT3 signal transduction pathway
Regulation of intracellular Stat3 signalling .
Effects of STAT3 Deﬁciency on Cellular Function Stuart et al.T he Journal of Immunology, 2009, 182: 21–28
Psoriasis is a chronic inflammatory skin disease characterized by excessive proliferation, abnormal differentiation of epidermal keratino- cytes, vascular proliferation, and leukocyte infiltration in the dermis and epidermis .
It has been considered that psoriasis results from complex, aberrant relationships between the skin and immune system as well as genetic predisposition and environmental factors
Psoriasis is an inflammatory skin disorder characterized by increased activation of CD4+ T lymphocytes, and systemic and local overexpression of pro-inflammatory cytokines such as interleukin 2 (IL-2), gamma interferon (IFN-), IL-6 and tumour necrosis factor alpha, indicating that immunopathogenesis of the disease is T helper 1 (Th1) mediated.
T helper cell precursors (Thp) can be skewed towards mutually exclusive Th1, Th2, Th17 and T regulatory cell (Treg) phenotypes on the basis of the cytokine environment .
Several studies suggest a pivotal role of bacterial superantigens in the initiation and/or exacerbation of this illness. In contrast to controls, psoriasis patients in the early course of disease were characterized by significantly increased expression of the pro-inflammatory cytokine IFN-, whilst a shift towards IL-10 secretion (Th2 response) was observed in those presenting with increased duration of disease.
These observations suggest a possible shift from a Th1 to a Th2 cytokine response with superantigen-associated progression for the duration of psoriasis, perhaps as an adaptive process by the immune system in an attempt to downregulate abnormal inflammatory Th1 immune responses ( Jain etal 2009 J Med Microbiol 58 :180-184).
T HELPER(TH) CELL DEVELOPMENT&DIFFERENTIATION: A BACKGROUND
During the initial activation of CD4+ lymphocyte, the antigen-presenting dendritic cells secrete a variety of cytokines that instruct the naïve T cell to activate one of several alternative T helper cell developmental pathways leading to Th1, Th2, Th17 or Treg lineage.
Each T helper phenotype produces its signature cytokines that mediate its distinct immunoregulatory functions.
Activation of naïve T cells in the presence of antigen and specific cytokine signals (IFN-γ for Th1, IL-4 for Th2, and TGF-β plus IL-6 for Th17 cells) induces T cells differentiation into either Th1, Th2, or Th17 development pathways.
STAT-1, STAT-4, and T-bet require for the generation of Th1 differentiation. STAT-6 and GATA-4 induces Th2 differentiation. Similarly, STAT-3, ROR-γt, and ROR-α mediates Th17differentiations pathways
J Clin Immunol (2008) 28:660–670 663
The Th1-Th2 Paradigm Naive T cell Dendritic cell TGF IFN IL-4 +IL-6 -IL-6 Th1 Tbet Th2 Gata 3 Th17 ROR T aTreg FoxP3 IL-12R IL-12 IL-23R IL-23 Adapted from Reiner et al., Cell , 2007 Autoimmunity Inflammation Cancer Extracellular bacteria Allergy and asthma Systemic pathology Harmful role Counter regulation Parasitic worms Intracellular pathogens Protective role
The Fate of Immune Responses Depends on the Balance between Effector and Regulatory T cells T regulatory T effector
Differentiation into Th17 or inducible-regulatory T cell ( iTreg) lineage has an obligatory requirement for signals provided by TGF-b. Shortly after the activation of naive CD4+
T cells, convergence of IL-2 and TGF-b1 signals generates the common Treg/Th17 precursor characterized expression of Foxp3 and RORct. Further stimulation by TGF-b1 favors iTreg differentiation while maturation of the Treg/Th17 precursor in inﬂammatory niche with high of IL-6, inhibits Foxp3 .
This skews development towards Th17 phenotype.
The Th17 master transcription factors, ROR ct and RORa, induce expression of IL-23 receptor through STAT3 -dependent mechanisms,
T helper cell precursors being skewed towards Th1, Th2, Th17 and T regulatory cell (Treg) phenotypes on the basis of the cytokine environment .
Cytokine signaling and transcription factors in the regulation of Th17 cell differentiation .
TCR stimulation activates gene expression of general transcription factors such as NFAT, AP-1, and NF-κB, and induces Th cell activation and proliferation.
BATF is activated upon TCR stimulation and stimulates IL-17 gene transcription.
TGFβ stimulation induces both FoxP3 and RORγt (also RORa) activation.
High concentrations of TGFb increase FoxP3 through the activation of SMAD4 and subsequently induce TGFb production and simultaneously suppress RORγt activity and Th17 cell differentiation.
However, the presence of cytokine IL-6 or IL-21 activates STAT3 and induces gene expression of the IL-21 and IL-23 receptor, activating positive IL-21 autocrine regulation for Th17 cell differentiation.
In addition, IL-1 induces IRF4 or epidermal FABP4, which in turn induces IL-17 gene transcription.
While T-bet and Ets-1 antagonize RORγt activity and thus function as suppressors of Th17 cell development,
PPARγintrinsically suppresses IL-17 gene transcription by blocking the activation-induced removal of repressor complexes from the IL-17 gene promoter.
Cytokine signaling and transcription factors in the regulation of Th17 cell differentiation . TCR stimulation activates gene expression of general transcription factors such as NFAT, AP-1, and NF-κB, and induces Th cell activation and proliferation. BATF is activated upon TCR stimulation and stimulates IL-17 gene transcription. TGFβ stimulation induces both FoxP3 and RORγt (also RORa) activation. High concentrations of TGFb increase FoxP3 through the activation of SMAD4 and subsequently induce TGFb production and simultaneously suppress RORγt activity and Th17 cell differentiation. However, the presence of cytokine IL-6 or IL-21 activates STAT3 and induces gene expression of the IL-21 and IL-23 receptor, activating positive IL-21 autocrine regulation for Th17 cell differentiation. In addition, IL-1 induces IRF4 or epidermal FABP4, which in turn induces IL-17 gene transcription. While T-bet and Ets-1 antagonize RORγt activity and thus function as suppressors of Th17 cell development, PPARγintrinsically suppresses IL-17 gene transcription by blocking the activation-induced removal of repressor complexes from the IL-17 gene promoter. SOCS1 and SOCS reciprocally modulate Th17 cell differentiation. TCR, T cell receptor; NFAT, nuclear factor of activated T cells; AP, activator protein; BATF, B cell-activating transcription factor; IL-17, interleukin-17; TGFβ, transforming growth factor β; RORγt, retinoic acid-related orphan receptor γt; STAT, signal transducer and activator of transcription; IRF-4, interferon-inducible factor-4; E-FABP, epidermal-fatty acid-binding protein; PPARγ, peroxisome proliferator activated receptor γ; SOCS, suppressors of cytokine signaling
Transcriptional regulation of TH17-cell differentiation . Na ¨ ıve CD4 T cells stimulated under the presence of IL-6 and/or IL-21 induce activation of the signal transducer and activator of transcription 3 (STAT3). Activation of STAT3 induces the expression of retinoicacid-receptor-related orphan receptor-α (RORα) and RORγt, which establish the expression of TH-17-cell speciﬁc gene program. The role of STAT3 in directly inducing IRF4 remains unclear. STAT1, downstream of IFN-γ and IL-27 signaling, or STAT5, which is downstream of IL-2 signaling, as well as ETS1, negatively regulate TH17 differentiation. Moreover, the transcription factor forkhead box P3 (Foxp3), induced by transforming growth factor-β (TGF-β) signaling, antagonizes the TH17-cell developmental program by directly binding to RORα or RORγt. Whether TGF-β-induced Smads or MAPKs participate in TH17 differentiation needs to be demonstrated.+
Helper T cell (Th) commitment to Th1, Th17 and T regulatory cell (Treg) phenotypes following encounter with antigen. Production of transforming growth factor (TGF)-β by naturally occurring Tregs leads to lineage commitment of precursor
TH17 responses in mice are also restrained byCD4+ regulatory T cells (Tregs)
This suppression was lost upon Treg-specific ablation of Stat3 , a transcription factor critical for TH17 differentiation, and resulted in the development of a fatal intestinal inflammation.
These findings suggest that Tregs adapt to their environment by engaging distinct effector response–specific suppression modalities upon activation of STAT proteins that direct the corresponding class of the immune response( Chaudhry et al,2009 Science 13 326 . no. 5955, : 986 – 991 ) .
STAT3 REGULATION of CYTOKINE-MEDIATED GENERATION of TH 17
IL-6 functions to up-regulate IL-23R and that IL-23 synergized with IL-6 in promoting THi (TH17)generation.
STAT3, activated by both IL-6 and IL-23, plays a critical role in THi development. A hyperactive form of STAT3 promoted THi development, whereas this differentiation process was greatly impaired in STAT3-deficient T cells. Moreover, STAT3 regulated the expression of retinoic acid receptor-related orphan receptor IL-17 -T (RORt), a THi-specific transcriptional regulator.
STAT3 deficiency impaired ROR t expression and led to elevated expression of T-box expressed in T cells (T-bet) and Forkhead box P3 (Foxp3).
There is a pathway whereby cytokines regulate THi differentiation through a selective STAT transcription factor that functions to regulate lineage-specific gene expression ( Yang et al.,2007 J.Biol Chem.,282,13:9358 & Egwuagu :Cytokine 47 (2009) 149–156 ) .
An initiating event such as trauma or skin surface microbes triggers IL-23 production by keratinocytes and resident dendritic cells, which in turn stimulates proliferation of CCR4 and CCR6
Th17 cells found within skin. These activated Th17 cells secrete Th17 cytokines including IL-22 and IL-17A , which cause keratinocyte growth and activation, respectively.
Th17 cytokines also induce CCL20 production by keratinocytes, which fosters additional chemotaxis of CCR6++ Th17 cells and CCR6 dendritic cells from blood into skin. Cytokines released by these newly recruited cells maintain psoriatic inflammation
Th17 cells: effector cytokines and their function.
Th17 cells characterized by production of IL-17A, IL-17F, IL-22, and IL-21.
Both IL-22 and IL-21 are not the exclusive cytokines produced byTh17 cells. IL- 17 A and IL- 17F mediate tissue damages during organ specific autoimmunity via variety of mechanism including the activation of matrix metalloproteinases and recruitment o f neutrophils.
IL-22 induces skin inflammation. IL-21 mediates amplification of T helper 17 pathway.
IL-17 is overexpressed in multiple sclerosis, rheumatoid arthritis and psoriasis
Cua et al., Nature 421:744, 2003 Weaver et al., Immunity 24:677, 2006 Mensah-Brown et al., Eur J Immunol 36:216, 2006 S Hue et al. J Exp Med 11:2473, 2006
Stat3 links activated keratinocytes and immunocytes required for development of psoriasis
Epidermal keratinocytes in psoriatic lesions are characterized by activated Stat3.
Transgenic mice with keratinocytes expressing a constitutively active Stat3 ( K5.Stat3C mice ) develop a skin phenotype either spontaneously, or in response to wounding, that closely resembles psoriasis.
Keratinocytes from K5.Stat3C mice show upregulation of several molecules linked to the pathogenesis of psoriasis.
In addition, the development of psoriatic lesions in K5.Stat3C mice requires cooperation between Stat3 activation in keratinocytes and activated T cells.
Finally, abrogation of Stat3 function by a decoy oligonucleotide inhibits the onset and reverses established psoriatic lesions in K5.Stat3C mice. Thus, targeting Stat3 may be potentially therapeutic in the treatment of psoriasis.
Blocking the function of STAT3 using antisense oligo-nucleotides inhibited the onset of, and reversed, established psoriatic lesions .
Further analysis revealed a dual requirement of both activated STAT3 in keratinocytes as well as in T cells, indicating that the pathogenesis of psoriasis is rooted in a co-operative process involving STAT3-regulated genes in both skin cells and the immune system .
Phosphatyrosyl peptides block STAT3-mediated DNA binding activity, gene regulation and cell transformation.
( Varadwaj et al 2010 Egyptian Dermatology Online Journal 6 (1 ) )
STAT3 protein has emerged as an important determinant of whether the naïve T cell differentiates into regulatory ( Treg) or an inflammatory ( Th17) T cell lineage.
STAT3 also has potent anti-inflammatory effects and regulates critical cellular processes such as, cell growth, apoptosis and transcription of inflammatory genes.
Dysregulation of STAT3 pathway has therefore been implicated in the development of chronic inflammatory diseases, as well as, a number of malignant and neurodegenerative diseases.
New insights from animal models of psoriasis as an exemplar of critical roles that STAT3 pathways play in inflammatory diseases including psoriasis and on how inhibiting STAT3 can be exploited to mitigate pathogenic autoimmunity( Egwuagu Cytokine 47 (2009) 149–156 )