Stat3 protein & t helper 17 cell -in psoriasis by yousry a mawla


Published on

PPs to show interaction between TH17 cell and stat3 protein in pathogenesis of psoriasis

1 Comment
No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide

Stat3 protein & t helper 17 cell -in psoriasis by yousry a mawla

  1. 1. STAT 3& TH17 CELL in PSORIASIS M.YOUSRY ABDEL-MAWLA,MD Zagazig Faculty of Medicine,Egypt
  2. 2. Signal transducers and activators of transcription ) Stat) Family <ul><li>Stats are latent in the cytoplasm until they are activated by extracellular signaling ligands , including cytokines , growth factors and hormones. </li></ul><ul><li>Binding of these extracellular ligands to the specific receptors leads to activation of various Tyrosine kinases (TKs). </li></ul><ul><li>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 </li></ul>
  3. 3. Cytokines and growth factors that activate STAT proteins
  4. 5. Structure of STAT3 protein. <ul><li>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. </li></ul>
  5. 6. STAT3 Activation <ul><li>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 . </li></ul><ul><li>Stat3 is the major signal transducer downstream of gp130-like receptors . </li></ul><ul><li>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. </li></ul>
  6. 7. Mechanism of Stat3 signaling <ul><li>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 </li></ul>
  7. 8. Regulation of the STAT3 signal transduction pathway <ul><li>Cytokine-binding induces receptor oligomerization that facilitates cross-phosphorylation and activation of receptor-associated JAK kinases. </li></ul><ul><li>Recruitment of STAT3 proteins to the activated receptor complex results in their activation, dimerization and translocation into the nucleus </li></ul><ul><li>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. </li></ul><ul><li>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. </li></ul>
  8. 9. Regulation of the STAT3 signal transduction pathway
  9. 10. Regulation of intracellular Stat3 signalling .
  10. 11. JAK/Stat pathway activation and inhibition. <ul><li>Upon cytokine binding to its receptor, JAK/Stat pathway is activated (left) leading to sequential cell response. </li></ul><ul><li>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 </li></ul><ul><li>Deng et al., Current Cancer Drug Targets , 2007, 7 , 91-107 </li></ul>
  11. 12. Small Molecule Inhibitors of Stat3 Signaling Pathway <ul><li>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. </li></ul><ul><li>Thus, Stat3 is an attractive molecular target for the development of novel therapeutics. </li></ul><ul><li>These small molecular inhibitors, are divided into five classes of compounds. </li></ul><ul><li>They include </li></ul><ul><li>(1) Natural products and derivatives, such as curcumin, resveratrol and others. </li></ul><ul><li>(2) Tyrphostins. </li></ul><ul><li>(3) Patinum-containing complexes. </li></ul><ul><li>(5) Azaspiranes. </li></ul><ul><li>Some compounds may have multiple targets including Stat3 protein. </li></ul><ul><li>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 ) </li></ul>
  12. 13. Effects of STAT3 Deficiency on Cellular Function Stuart et al.T he Journal of Immunology, 2009, 182: 21–28
  13. 14. Psoriasis
  14. 15. Psoriasis <ul><li>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 . </li></ul><ul><li>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 </li></ul>
  15. 16. Combined data on psoriasis susceptibility loci <ul><li>ND:not determined ( Pietrzak etal Folia Histochem Cytobiol. 2008:46(1): 12 (11-21) </li></ul>
  16. 17. Psoriasis Clinical Presentation
  17. 18. Clinical Manifestations of Psoriasis
  18. 19. Histopathology of Psoriasis <ul><li>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 ). </li></ul>
  19. 20. Immunopathology of Psoriasis <ul><li>The development of psoriatic plaque begins with antigen recognition and uptake by antigen-presenting cells (APC) </li></ul><ul><li>In psoriasis the dendritic cells (DC) are the most common type of antigen-presenting cells. </li></ul><ul><li>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. </li></ul><ul><li>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. ). </li></ul>
  20. 21. Immunopathology of Psoriasis <ul><li>Naive T (CD4+ )cells have to go through maturation in lymphatic tissues. </li></ul><ul><li>CD4+ T cells have a strong affinity to MHC II-peptide complex and they stick together by forming an immunological synapsis. </li></ul><ul><li>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. </li></ul><ul><li>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. </li></ul><ul><li>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. ). </li></ul>
  21. 22. Immunopathology of Psoriasis <ul><li>In inflamed skin, T cells enter the tissue and participate in the inflammation reaction. </li></ul><ul><li>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. </li></ul><ul><li>Expressions of P- and E-selectins are upregulated in psoriatic skin, possibly stiffening the inflammation observed in psoriatic plaque. </li></ul><ul><li>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. </li></ul><ul><li>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. ). </li></ul>
  22. 23. Immunopathology of Psoriasis <ul><li>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. </li></ul><ul><li>T cells in psoriatic skin have prolonged and increased IFN- response when compared to healthy skin. Interferon- enhances INF-expression in T cells . </li></ul><ul><li>Also cytokines produced by APCs, especially IL-23 and IL-6 , have an important role in reactivation. </li></ul><ul><li>After reactivation T cells express a variety of cytokines. </li></ul><ul><li>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. </li></ul><ul><li>Keratinocyte activation leads to their increased proliferation and alterations in the maturation process. </li></ul><ul><li>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 ( Sabat et al. 2007 Exp Dermatol 16:779-798 &. Boehncke et al JEADV 2010, 24 Suppl. 5, 2–24 ) . </li></ul>
  23. 24. <ul><li>Following a trigger or stimulus, dendritic cells and T cells are activated, leading to the formation of an ‘immunological synapse’ that enhances their interactions. </li></ul><ul><li>This ‘immunologic synapse’ results in the release of cytokines, chemokines and growth factors that trigger keratinocyte proliferation, altered differentiation and angiogenesis. </li></ul><ul><li>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.). </li></ul>
  24. 25. Immunopathology of Psoriasis
  25. 26. T-Cell in Psoriasis <ul><li>The pathogenesis of psoriasis is a multistep process, and an array of cytokines has an impressive role in these processes . </li></ul><ul><li>IL-2 and IFN-γ are two important cytokines, which secreted upon Th1 activation. </li></ul><ul><li>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 ) </li></ul>
  26. 27. <ul><li>Serum cytokine levels of psoriatic patients and controls ( Z Jadali et alIranian J Publ Health, Vol. 36, No.2, 2007, pp.87-91 ) </li></ul>
  27. 28. <ul><li>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 ) </li></ul>
  28. 29. <ul><li>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 ) </li></ul>
  29. 30. T Helper 1 versus 2 in psoriasis <ul><li>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. </li></ul><ul><li>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 .   </li></ul><ul><li>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. </li></ul><ul><li>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). </li></ul>
  30. 31. PSORIASIS IS a TH17 DISEASE :A Hypothesis <ul><li>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. </li></ul><ul><li>These activated Th17 cells secrete Th17 cytokines including IL-22 and IL-17A , which cause keratinocyte growth and activation, respectively. </li></ul><ul><li>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 ) </li></ul>
  31. 32. STAT3 REGULATION of CYTOKINE-MEDIATED GENERATION of TH 17 <ul><li>IL-6 functions to up-regulate IL-23R and that IL-23 synergized with IL-6 in promoting THi (TH17)generation. </li></ul><ul><li>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. </li></ul><ul><li>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). </li></ul><ul><li>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 ) . </li></ul>
  32. 33. T Helper 17 Activation Mechanisms in Psoriasis <ul><li>(Fitch, etal., Current Rheumatology Reports 2007, 9:461–467 ) </li></ul>
  33. 34. TH17 cells: effector cytokines and their function. <ul><li>Th17 cells characterized by production of IL-17A, IL-17F, IL-22, and IL-21. </li></ul><ul><li>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. </li></ul><ul><li>IL-22 induces skin inflammation. IL-21 mediates amplification of T helper 17 pathway. </li></ul>
  34. 35. Proinflammatory Effects of IL17
  35. 36. Roles of IL-23 on T Helper 17 cells in Chronic Inflammation in Psoriasis Adapted from Iwakura & Ishigame, J Clin Invest 116:1218-1222 (2006) 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
  36. 37. <ul><li>Interleukin-23 (IL-23 ) helps to maintain the lesion by leading to the development of Th17 cells. </li></ul><ul><li>These in turn produce necrosis factor-alpha (TNF-a), I L-17 and IL-22. </li></ul><ul><li>IL-22 is believed to drive many of the epidermal changes in psoriasis . </li></ul><ul><li>Many autoimmune diseases, including psoriasis , are characterized by high levels of Th17 . </li></ul><ul><li>Journal of Investigative Dermatology 2009;129:1339–1350 . </li></ul>
  37. 38. The IL23 – IL17 axis: a critical role in autoimmune inflammation <ul><li>IL-23 & IL-17 promote inflammatory bowel disease and autoimmune experimental encephalomyelitis </li></ul><ul><li>IL-17 is overexpressed in multiple sclerosis, rheumatoid arthritis and psoriasis </li></ul>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
  38. 39. Genetic Polymorphism <ul><li>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. </li></ul><ul><li>Certain IL-12/23p40 and IL-23R polymorphisms correlate with certain disease presentations (e.g., guttate vs. pustular psoriasis) or with severity of disease . </li></ul><ul><li>( Blauvelt J Invest Dermatol. 2008 May ; 128(5): 1064–1067 ). </li></ul>
  39. 40. <ul><li>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 ). </li></ul>
  40. 41. Stat3 links activated keratinocytes and immunocytes required for development of psoriasis <ul><li>Epidermal keratinocytes in psoriatic lesions are characterized by activated Stat3. </li></ul><ul><li>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. </li></ul><ul><li>Keratinocytes from K5.Stat3C mice show upregulation of several molecules linked to the pathogenesis of psoriasis. </li></ul><ul><li>In addition, the development of psoriatic lesions in K5.Stat3C mice requires cooperation between Stat3 activation in keratinocytes and activated T cells. </li></ul><ul><li>Finally, abrogation of Stat3 function by a decoy oligonucleotide inhibits the onset and reverses established psoriatic lesions in K5.Stat3C mice. </li></ul><ul><li>Thus, targeting Stat3 may be potentially therapeutic in the treatment of psoriasis. </li></ul>
  41. 42. Experimental Models of Psoriasis <ul><li>An interesting transgenic mouse model for psoriasis is transgenic mouse with constitutively active Stat3 overexpression. </li></ul><ul><li>Stat3, participates in cell proliferation, apoptosis, cell differentiation and other important biological functions </li></ul><ul><li>In addition, its expression is elevated in psoriasis and in lesional keratinocytes, particularly in the nuclei of keratinocytes . </li></ul><ul><li>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 . </li></ul><ul><li>Of these, IL-22 is produced by Th17 lymphocytes, in contrast to the other related cytokines, and its production is induced by IL-23. </li></ul><ul><li>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 ). </li></ul>
  42. 43. Experimental Models of Psoriasis <ul><li>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 ) . </li></ul>
  43. 44. Up-regulated molecules in keratinocytes of K5.Stat3C mice <ul><li>(Sano etal., Journal of Dermatological Science (2008) 50, 1—14 ) </li></ul>
  44. 45. <ul><li>Blocking the function of STAT3 using antisense oligo-nucleotides inhibited the onset of, and reversed, established psoriatic lesions . </li></ul><ul><li>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 . </li></ul><ul><li>Phosphatyrosyl peptides block STAT3-mediated DNA binding activity, gene regulation and cell transformation. </li></ul><ul><li>( Varadwaj et al 2010 Egyptian Dermatology Online Journal 6 (1 ) ) </li></ul>
  45. 46. Development of psoriasis following wound healing . <ul><li>( 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 ) </li></ul>
  46. 47. Psoriatic lesions of K5.Stat3C mice <ul><li>( A)Psoriasis lesions and its histology (H and E staining, (B). (Sano etal., Journal of Dermatological Science (2008) 50, 1—14 ) </li></ul>
  47. 48. A Tender Piece of Information
  48. 49. Do Other Therapies Work Within This Framework? <ul><li>Anti–T-cell agents could affect Th17 cells as they would other T cells, but this needs to be clarified </li></ul><ul><li>Anti-TNF agents could decrease activity of Th1 7 cells or work directly on keratinocyte responses </li></ul>
  49. 50. Studies on Stat 3 in Psoriasis
  50. 51. Stat 3 in Psoriasis
  51. 54. New Prospectives &Directions
  52. 56. Manipulation of Psorasis
  53. 57. Therapeutic Targets in Psoriasis As a T Helper 17 Cell-Mediated Disease
  54. 58. Anti TNF approved for psoriasis treatment JEADV 2010, 24 (Suppl. 5), 2–24
  55. 62. IL-12/IL-23 Inhibitors in Psoriasis <ul><ul><ul><li>Kauffman et al., J Invest Dermatol 123: 1037, 2004 </li></ul></ul></ul><ul><ul><ul><li>Krueger et al., N Engl J Med 356: 580, 2007 </li></ul></ul></ul><ul><ul><ul><li>Torti et al., J Am Acad Dermatol, 10.1016/j.jaad.2007.07.016   </li></ul></ul></ul>
  56. 63. IL-12/IL-23 as Therapeutic Targets in Psoriasis <ul><li>Role of IL-12/IL-23 in Mouse Models </li></ul><ul><ul><ul><li>Experimental psoriasis is abolished by anti-p40 Ab therapy </li></ul></ul></ul><ul><ul><ul><li>Transgenic overexpression of p40 results in skin inflammation </li></ul></ul></ul><ul><ul><ul><li>IL-23 injection results in skin inflammation </li></ul></ul></ul><ul><li>Expression of IL-12/IL-23 in Human Psoriasis </li></ul><ul><ul><ul><li>p40 mRNA and protein are increased in psoriatic lesions </li></ul></ul></ul><ul><ul><ul><li>p19 mRNA and protein are increased in psoriatic lesions </li></ul></ul></ul><ul><ul><ul><li>IL-12 and IL-23 decrease after conventional psoriatic therapy </li></ul></ul></ul><ul><ul><ul><li>A polymorphism in p40 gene is associated with susceptibility to psoriasis </li></ul></ul></ul><ul><li>Clinical Studies with anti-p40 mAb </li></ul>Reviewed in Torti et al., J Am Acad Dermatol, 2007 doi: 10.1016/j.jaad.2007.07.016 
  57. 64. Current Rheumatology Reports 2007 , 9:461–467
  58. 65. Message Home
  59. 66. Message Home <ul><li>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. </li></ul><ul><li>STAT3 also has potent anti-inflammatory effects and regulates critical cellular processes such as, cell growth, apoptosis and transcription of inflammatory genes. </li></ul><ul><li>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. </li></ul><ul><li>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 ) </li></ul>
  60. 67. Message Home <ul><li>Stat3 is Key intracellular signaling molecule important in Th17 development and mediates IL-22 –induced keratinocyte hyperproliferation. </li></ul><ul><li>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 . </li></ul>
  61. 68. THANK YOU