Role of Stat3 protein & T -helper 17 cell -in psoriasis Developme

Role of Signal Transducer &Activator of Transcription( STAT)-3 & T Helper (Th) 17 Cell in Psoriasis Development : 

Role of Signal Transducer &Activator of Transcription( STAT)-3 & T Helper (Th) 17 Cell in Psoriasis Development DR M.YOUSRY ABDEL-MAWLA,MD ZAGAZIG FACULTY OF MEDICINE,EGYPT

STAT 3& TH17 in PSORIASIS : 

STAT 3& TH17 in PSORIASIS

Signal transducers and activators of transcription) Stat) Family : 

Signal transducers and activators of transcription) Stat) Family Stats are latent in the cytoplasm until they are activated by extracellular signaling ligands, including cytokines, growth factors and hormones. Binding of these extracellular ligands to the specific receptors leads to activation of various Tyrosine kinases (TKs). They include JAKs, receptor TKs, and non-receptor TKs such as Src and ABL, which can directly phosphorylate Stat proteins in the absence of ligand-induced receptor signaling

Cytokines and growth factors that activate STAT proteins : 

Cytokines and growth factors that activate STAT proteins

Structure of STAT3 protein. : 

Structure of STAT3 protein. Similar to other members of the STAT family, STAT3 is comprised of six domains: N-terminal domain, coiled-coil domain, DNA binding domain, linker domain, SH2 domain and Tran activation domain.

STAT3 Activation : 

STAT3 Activation 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.

Mechanism of Stat3 signaling : 

Mechanism of Stat3 signaling 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 : 

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 the STAT3 signal transduction pathway

Regulation of intracellular Stat3 signalling. : 

Regulation of intracellular Stat3 signalling.

JAK/Stat pathway activation and inhibition. : 

JAK/Stat pathway activation and inhibition. Upon cytokine binding to its receptor, JAK/Stat pathway is activated (left) leading to sequential cell response. The signaling process can be inhibited (right) by (1) JAK degradation through ubiquitin-proteasome system (Ub), (2) dephosphorylate in cytoplasmic PTP1B or (3) nuclear phosphatase (NPTP), or (4) by blocking the Stat dimer formation Deng et al., Current Cancer Drug Targets, 2007, 7, 91-107

Small Molecule Inhibitors of Stat3 Signaling Pathway : 

Small Molecule Inhibitors of Stat3 Signaling Pathway Compelling evidence from mechanistic studies with antisense, RNA interference (RNAi), peptides, and small molecular inhibitors indicate that blocking Stat3 signaling can lead to successful suppression of tumor cell growth and apoptosis. Thus, Stat3 is an attractive molecular target for the development of novel therapeutics. These small molecular inhibitors, are divided into five classes of compounds. They include (1) Natural products and derivatives, such as curcumin, resveratrol and others. (2) Tyrphostins. (3) Patinum-containing complexes. (5) Azaspiranes. Some compounds may have multiple targets including Stat3 protein. Stat3 targeted small molecules will be beneficial for database development and template design for future drug development ( Deng, etal., Current Cancer Drug Targets, 2007, 7, 91-107)

Effects of STAT3 Deficiency on Cellular FunctionStuart et al.The Journal of Immunology, 2009, 182: 21–28 : 

Effects of STAT3 Deficiency on Cellular FunctionStuart et al.The Journal of Immunology, 2009, 182: 21–28

T HELPER(TH) CELL DEVELOPMENT&DIFFERENTIATION: A BACKGROUND : 

T HELPER(TH) CELL DEVELOPMENT&DIFFERENTIATION: A BACKGROUND

T-helper-cell differentiation : 

T-helper-cell differentiation 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.

T-helper-cell differentiation : 

T-helper-cell differentiation

Slide 18: 

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 : 

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

The Fate of Immune Responses Depends on the Balance between Effector and Regulatory T cells : 

The Fate of Immune Responses Depends on the Balance between Effector and Regulatory T cells T regulatory T effector

Features of T Helper Subsets : 

Features of T Helper Subsets

STAT3 & TH17 CELL : 

STAT3 & TH17 CELL

STAT3 & Th17/Treg developmental programs : 

STAT3 & Th17/Treg developmental programs 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,

Slide 24: 

Steps in the generation of Th17 cells. The activation of naive T cells in the presence of TGF-β and IL-6 initiates the Th17 differentiation pathway. Th17 cells produce IL-21, which further amplifies Th17 generation in an autocrine manner. IL-21 also induces the IL-23R on differentiated Th17 cells to make them responsive to IL-23 signaling. IL-23 stabilizes the Th17 phenotype by secreting IL-17A, IL-17F and IL-22 and helping Th17 cells to acquire effector functions. STAT-3 plays an important role in Th17 differentiation, amplification and stabilization as IL-6, IL-21 and IL-23 signals through STAT-3. (Awasthi and Kuchroo, International Immunology, 2009)

STAT3 & Th17/Treg developmental programs : 

STAT3 & Th17/Treg developmental programs

T helper cell precursors being skewed towards Th1, Th2, Th17 and T regulatory cell (Treg) phenotypes on the basis of the cytokine environment. : 

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. : 

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.

Slide 28: 

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

Slide 29: 

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.+

Microbial Antigens & Th 17 Response : 

Microbial Antigens & Th 17 Response 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

ACTIVATION of T H 17 &STAT3 : 

ACTIVATION of T H 17 &STAT3 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 : 

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).

T Helper(TH) 17 Cell in Autoimmune Disorders (Bettelli et al., Nature 2008) : 

T Helper(TH) 17 Cell in Autoimmune Disorders (Bettelli et al., Nature 2008)

Psoriasis : 

Psoriasis

Psoriasis : 

Psoriasis 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

Combined data on psoriasis susceptibility loci : 

Combined data on psoriasis susceptibility loci ND:not determined (Pietrzak etal Folia Histochem Cytobiol. 2008:46(1): 12 (11-21)

Psoriasis Clinical Presentation : 

Psoriasis Clinical Presentation

Clinical Manifestations of Psoriasis : 

Clinical Manifestations of Psoriasis

Histopathology of Psoriasis : 

Histopathology of Psoriasis Histology of healthy (A) and psoriatic (B) skin. Psoriatic skin shows epidermal acantohosis, elongation of rete ridges (indicated by arrows) with reciprocal elongation of intervening dermal papillae and inflammatory infiltrate (40X magnification).

Immunopathology of Psoriasis : 

Immunopathology of Psoriasis The development of psoriatic plaque begins with antigen recognition and uptake by antigen-presenting cells (APC) In psoriasis the dendritic cells (DC) are the most common type of antigen-presenting cells. Antigens are presented on the DC surface usually as MHC class II molecules, which can be recognized by T cell receptor of CD4+ T cells. In addition DCs can present antigens on MHC class I molecules, which lead to the activation of CD8+ T cells. DCs also enhance the production of adhesion and co-stimulatory molecules to facilitate its interaction with T cells (Sabat et al. 2007 Exp Dermatol 16:779-798.).

Immunopathology of Psoriasis : 

Immunopathology of Psoriasis Naive T (CD4+ )cells have to go through maturation in lymphatic tissues. CD4+ T cells have a strong affinity to MHC II-peptide complex and they stick together by forming an immunological synapsis. Interaction between ICAM-1, produced by DCs, and LFA-1, from T cells, is one of the most important in order to facilitate the DC-T cell interaction. Naive T cells can mature either to Th1, Th2, Th17 or regulatory T cells and subtype is guided by the selection of a soluble mediator present during the activation of naive T cells. After the activation, T cells express cutaneous lymphocyte-associated antigen (CLA), which directs T cells to inflamed skin. P- and E-selectins expressed by endothelial cells are also important for T cell skin homing (Sabat et al. 2007 Exp Dermatol 16:779-798.).

Immunopathology of Psoriasis : 

Immunopathology of Psoriasis In inflamed skin, T cells enter the tissue and participate in the inflammation reaction. Interaction between P- and E- selectins and CLA, as well as other selectin ligands, facilitate leukocytes rolling along the blood vessel wall as they decrease the rolling velocity. Expressions of P- and E-selectins are upregulated in psoriatic skin, possibly stiffening the inflammation observed in psoriatic plaque. T cells recognize chemokines secreted by the endothelial cells, become active and a tight adhesion, facilitated by integrins produced by T cells and their ligands expressed by endothelial cells, is formed between the cells. The most important molecule in skin homing is LFA-1 binding to ICAM-2. T cells probably enter the endothelial wall through pores formed between endothelial cells in an integrin-dependent process called diapedesis (Sabat et al. 2007 Exp Dermatol 16:779-798.).

Immunopathology of Psoriasis : 

Immunopathology of Psoriasis In the skin T cells are reactivated by different kinds of APCs, which also include keratinocytes. Interferon- (IFN-), produced by APCs, has an important role in T cell reactivation and proliferation. T cells in psoriatic skin have prolonged and increased IFN- response when compared to healthy skin. Interferon- enhances INF-expression in T cells. Also cytokines produced by APCs, especially IL-23 and IL-6, have an important role in reactivation. After reactivation T cells express a variety of cytokines. T cell response leads to the activation of keratinocytes and the activation is carried out by Th17 and different cytokines produced by macrophages, DCs and keratinocytes themselves. Keratinocyte activation leads to their increased proliferation and alterations in the maturation process. Activated keratinocytes produce a vast variety of mediators, which further promote immigration of inflammatory cells and induce angiogenesis, thus enhancing phenomena relevant for the pathogenesis of psoriasis (NICKOLOFF&NESTLE ,(2004),J CLILINICAL INVESTIGATION,113:1664 ,Sabat et al. 2007 Exp Dermatol 16:779-798 &. Boehncke et al JEADV 2010, 24 Suppl. 5, 2–24).

Slide 44: 

Following a trigger or stimulus, dendritic cells and T cells are activated, leading to the formation of an ‘immunological synapse’ that enhances their interactions. This ‘immunologic synapse’ results in the release of cytokines, chemokines and growth factors that trigger keratinocyte proliferation, altered differentiation and angiogenesis. Within the chronic psoriatic plaque, a vicious cycle of continuous T cell and dendritic cell activation is envisioned (Nickoloff & Nestle : J Clin Invest 2004; 113: 1664–1675.).

Prepsoriasis State : 

Prepsoriasis State

Prepsoriasis State : 

Prepsoriasis State

Development of Psoriasis : 

Development of Psoriasis

Immunopathology of Psoriasis : 

Immunopathology of Psoriasis NICKOLOFF&NESTLE ,(2004),J CLILINICAL INVESTIGATION,113:1664

Psoriasis: Evidence of T-Cell Mediation : 

Psoriasis: Evidence of T-Cell Mediation Early cells in psoriatic lesions Cyclosporine, anti-CD4 monoclonal antibodies are used as treatment Blocking T cell:APC 2nd signal prevents psoriatic lesion Psoriasis altered in HIV infection Streptococcal superantigens can induce psoriasis

T-Cell in Psoriasis : 

T-Cell in Psoriasis The pathogenesis of psoriasis is a multistep process, and an array of cytokines has an impressive role in these processes . IL-2 and IFN-γ are two important cytokines, which secreted upon Th1 activation. These cytokines activate different signal transducers and augment transcription of a large group of immune related genes and may contribute to the overall pathogenic process (Z Jadali et alIranian J Publ Health, Vol. 36, No.2, 2007, pp.87-91)

T-Cell in Psoriasis : 

T-Cell in Psoriasis The Th1 character of psoriasis is supported by the development of skin lesions in quiescent patients treated with IL-2 for cancer therapy. Conversely, a therapeutic effect, accompanied by a shift toward Th2 cytokine expression patterns, is seen in psoriasis patients following administration of the Th2 cytokine, IL-10. T cells cloned from psoriatic skin can variously produce IFN-, TGF-, IL-2, IL-3, IL-6, IL-8, and GM-CSF, although none of these are singly responsible for T cell stimulation of keratinocyte growth, which appears to involve IFN- in concert with other cytokines . IL-7 , produced by both T cells & keratinocytes, is also present at elevated levels in lesional psoriatic compared with nonlesional and normal skin ( Mollison et al Journal of Investigative Dermatology ,1999, 112: 729–738;) .

Slide 52: 

Serum cytokine levels of psoriatic patients and controls (Z Jadali et alIranian J Publ Health, Vol. 36, No.2, 2007, pp.87-91)

Slide 53: 

Serum levels of s IL - 2R in patients with psoriasis vulgaris compared to healthy controls (Halla M. Ragab et al J. of American Science 2010;6(10):423-429)

Slide 54: 

Serum levels of IL - 6 in patients with psoriasis vulgaris compared to healthy controls (Halla M. Ragab et al J. of American Science 2010;6(10):423-429)

T Helper 1 versus 2 in psoriasis : 

T Helper 1 versus 2 in psoriasis 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).

PSORIASIS IS aTH17 DISEASE :A Hypothesis : 

PSORIASIS IS aTH17 DISEASE :A Hypothesis 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 (Fitch, etal., Current Rheumatology Reports 2007, 9:461–467)

T Helper 17 Activation Mechanisms in Psoriasis : 

T Helper 17 Activation Mechanisms in Psoriasis (Fitch, etal., Current Rheumatology Reports 2007, 9:461–467)

TH17 cells: effector cytokines and their function. : 

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-17A 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.

Proinflammatory Effects of IL17 : 

Proinflammatory Effects of IL17

Roles of IL-23 on T Helper 17 cellsin Chronic Inflammation in Psoriasis : 

Adapted from Iwakura & Ishigame, J Clin Invest 116:1218-1222 (2006) Roles of IL-23 on T Helper 17 cellsin Chronic Inflammation in Psoriasis Dendritic cell Macrophage IL-23 IL-12 Th1 Th17 IFN IL-1, IL-6 TNF Inflammatory response Endothelial cells Stromal cells Epithelial cells Fibroblasts Macrophage IL-17, IL-6 IL-1 IL-6 IL-8 TNF IL-12R IL-23R IL-23R

Slide 61: 

Interleukin-23 (IL-23) helps to maintain the lesion by leading to the development of Th17 cells. These in turn produce necrosis factor-alpha (TNF-a), IL-17 and IL-22. IL-22 is believed to drive many of the epidermal changes in psoriasis. Many autoimmune diseases, including psoriasis, are characterized by high levels of Th17. Journal of Investigative Dermatology 2009;129:1339–1350.

Toll like Receptor (TLR) in Th17-mediated Autoimmune Inflammation (Goriely S, Neurath M, Goldman M, Nature Rev Immunol 2007) : 

Toll like Receptor (TLR) in Th17-mediated Autoimmune Inflammation (Goriely S, Neurath M, Goldman M, Nature Rev Immunol 2007) IL-23 IL-12 IL-27 TLR3 TLR2 Th1 Th1 Th17 IFN- Autoimmune Inflammation polyI : C PGN IFN-

The IL23 – IL17 axis: a critical role in autoimmune inflammation : 

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 The IL23 – IL17 axis: a critical role in autoimmune inflammation IL-23 & IL-17 promote inflammatory bowel disease and autoimmune experimental encephalomyelitis IL-17 is overexpressed in multiple sclerosis, rheumatoid arthritis and psoriasis

Genetic Polymorphism : 

Genetic Polymorphism Certain genetic changes in IL-12/23p40 and IL-23R will lead to enhanced IL-23 production and IL-23 receptor-mediated signaling and thus be correlative with psoriasis susceptibility in humans. Certain IL-12/23p40 and IL-23R polymorphisms correlate with certain disease presentations (e.g., guttate vs. pustular psoriasis) or with severity of disease . (Blauvelt J Invest Dermatol. 2008 May ; 128(5): 1064–1067).

Slide 65: 

Schematic of the related heterodimers IL-23 and IL-12 and their related heterodimeric cytokine receptors, indicating (in red circles) the subunits where polymorphisms in genes encoding these proteins have been linked to development of psoriasis (Blauvelt J Invest Dermatol. 2008 May ; 128(5): 1064–1067).

Stat3 links activated keratinocytes and immunocytes required for development of psoriasis : 

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.

Experimental Models of Psoriasis : 

Experimental Models of Psoriasis An interesting transgenic mouse model for psoriasis is transgenic mouse with constitutively active Stat3 overexpression. Stat3, participates in cell proliferation, apoptosis, cell differentiation and other important biological functions In addition, its expression is elevated in psoriasis and in lesional keratinocytes, particularly in the nuclei of keratinocytes . Stat3 is activated by many different cytokines, including members of IL-20 subfamily cytokines, namely IL-19, IL-20, IL-22 and IL-24, which are all upregulated in psoriatic skin . Of these, IL-22 is produced by Th17 lymphocytes, in contrast to the other related cytokines, and its production is induced by IL-23. Overexpression of IL-23 is profound in lesional psoriatic skin and Stat3 activation via IL-22 seems to be important in the IL-23-induced epidermal acanthosis relevant in the pathogenesis of psoriasis . (Zhang et al 2007 J Invest Dermatol, 27:2544-2551 and DANILENKO,2008 Vet Pathol 45:563–575) ).

Experimental Models of Psoriasis : 

Experimental Models of Psoriasis Constitutive activation of Stat3 in these mice (K5.Stat3C mice) increased the sensitivity of the epidermis to external stimuli, leading to a psoriatic phenotype, similar to the clinical Koebner phenomenon(Sano etal., Journal of Dermatological Science (2008) 50, 1—14).

Up-regulated molecules in keratinocytes of K5.Stat3C mice : 

Up-regulated molecules in keratinocytes of K5.Stat3C mice (Sano etal., Journal of Dermatological Science (2008) 50, 1—14)

Slide 70: 

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) )

Development of psoriasis following wound healing. : 

Development of psoriasis following wound healing. (A)Psoriasis upon burn scar in a 74-year-old woman. (B) Epidermal keratinocytes of psoriatic lesions show activated Stat3. Nuclei of the lesional keratinocytes are positive for Stat3, suggesting activated status of Stat3) Sano etal., Journal of Dermatological Science (2008) 50, 1—14)

Psoriatic lesions of K5.Stat3C mice : 

Psoriatic lesions of K5.Stat3C mice (A)Psoriasis lesions and its histology (H and E staining, (B). (Sano etal., Journal of Dermatological Science (2008) 50, 1—14)

A Tender Piece of Information : 

A Tender Piece of Information

Do Other Therapies Work Within This Framework? : 

Do Other Therapies Work Within This Framework? Anti–T-cell agents could affect Th17 cells as they would other T cells, but this needs to be clarified Anti-TNF agents could decrease activity of Th17 cells or work directly on keratinocyte responses

Studies on Stat 3 in Psoriasis : 

Studies on Stat 3 in Psoriasis

Stat 3 in Psoriasis : 

Stat 3 in Psoriasis

New Prospectives &Directions : 

New Prospectives &Directions

Manipulation of Psorasis : 

Manipulation of Psorasis

Psoriasis: New Immunologic Approaches to Treatment : 

Psoriasis: New Immunologic Approaches to Treatment TNF inhibition Antibodies to TNF Soluble TNF receptors Costimulatory blockade Adhesion molecule inhibition LFA-1 CD2 IL-2 activation blockade

Therapeutic Targets in Psoriasis As a T Helper 17 Cell-Mediated Disease : 

Therapeutic Targets in Psoriasis As a T Helper 17 Cell-Mediated Disease

Anti TNF approved for psoriasis treatmentJEADV 2010, 24 (Suppl. 5), 2–24 : 

Anti TNF approved for psoriasis treatmentJEADV 2010, 24 (Suppl. 5), 2–24

IL-12/IL-23 Inhibitors in Psoriasis : 

IL-12/IL-23 Inhibitors in Psoriasis Kauffman et al., J Invest Dermatol 123: 1037, 2004 Krueger et al., N Engl J Med 356: 580, 2007 Torti et al., J Am Acad Dermatol, 10.1016/j.jaad.2007.07.016

IL-12/IL-23 as Therapeutic Targets in Psoriasis : 

Reviewed in Torti et al., J Am Acad Dermatol, 2007 doi: 10.1016/j.jaad.2007.07.016 IL-12/IL-23 as Therapeutic Targets in Psoriasis Role of IL-12/IL-23 in Mouse Models Experimental psoriasis is abolished by anti-p40 Ab therapy Transgenic overexpression of p40 results in skin inflammation IL-23 injection results in skin inflammation Expression of IL-12/IL-23 in Human Psoriasis p40 mRNA and protein are increased in psoriatic lesions p19 mRNA and protein are increased in psoriatic lesions IL-12 and IL-23 decrease after conventional psoriatic therapy A polymorphism in p40 gene is associated with susceptibility to psoriasis Clinical Studies with anti-p40 mAb

Effect of a single 5 mg/kg dose of anti-p40 mAb in psoriasis : 

Effect of a single 5 mg/kg dose of anti-p40 mAb in psoriasis Kauffman et al., J Invest Dermatol 123: 1037, 2004

Slide 91: 

Current Rheumatology Reports 2007, 9:461–467

Topical Macrolactam Ascomycin Analog( ABT-281) in Psoriasis : 

Topical Macrolactam Ascomycin Analog( ABT-281) in Psoriasis Topical application of 3% ABT-281 in acetone/olive oil showed its superior efficacy, its rapid systemic clearance following uptake into the blood stream . Its ability to inhibit cytokine biosynthesis of both Th1 and Th2 cell subsets, suggests that it will have a broad therapeutic value in inflammatory skin diseases, including psoriasis ( Mollison et al Journal of Investigative Dermatology ,1999,112, :729–738;).

Future Psoriasis Therapy(Wippel-Slupetzky&Stingl Curr Probl Dermatol., 2009, 38, : 172–189) : 

Future Psoriasis Therapy(Wippel-Slupetzky&Stingl Curr Probl Dermatol., 2009, 38, : 172–189)

Slide 94: 

Future Psoriasis Therapy(Wippel-Slupetzky&Stingl Curr Probl Dermatol., 2009, 38, : 172–189)

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Message Home 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)

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Message Home Stat3 is Key intracellular signaling molecule important in Th17 development and mediates IL-22–induced keratinocyte hyperproliferation. Blocking of stat3 pathway is good-to-excellent (similar to TNF-a inhibitors): major signaling pathway inhibition may have expected good clinical results in psoriasis .

THANK YOU : 

THANK YOU