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Signal Transducer &Activator of Transcription( STAT)-3 &  T  Helper (Th) 17  Cell in Psoriasis <ul><li>DR M.YOUSRY ABDEL-M...
Signal   transducers   and   activators   of   transcription )  Stat) Family <ul><li>Stats   are   latent   in   the   cyt...
 
 
STAT3 Activation <ul><li>Stat3  is activated by cytokines  of the  IL-6 family such as IL-6, IL-11, leukemia inhibitory fa...
Mechanism of Stat3 signaling <ul><li>Different tyrosine kinases (TKs) can induce Stat3 activation. Growth factors such as ...
Psoriasis
Psoriasis <ul><li>Psoriasis  is a chronic  inflammatory  skin disease characterized by excessive  proliferation, abnormal ...
Psoriasis Clinical Presentation
Psoriasis as an immune disorder
Prepsoriasis State
Prepsoriasis State
Development of Psoriasis
Immunopathology of Psoriasis
T-Cell in Psoriasis
T  helper  1  versus 2  in psoriasis <ul><li>Psoriasis is an inflammatory skin disorder characterized by increased activat...
<ul><li>Psoriasis shares immunologic and genetic features with other human autoimmune inflammatory conditions such as infl...
T helper cell precursors being skewed towards Th1, Th2, Th17 and T regulatory cell (Treg) phenotypes on the basis of the c...
PSORIASIS IS A  Th17  DISEASE  :A  Hypothesis <ul><li>An initiating event such as trauma or skin surface microbes triggers...
PSORIASIS IS A  Th17  DISEASE <ul><li>T helper (Th) 17 cells, a novel T-cell subset, have been implicated in the pathogene...
 
Microbial Antigens &  Th 17  Response <ul><li>Helper T cell (Th) commitment to Th1, Th17 and T regulatory cell (Treg) phen...
ACTIVATION of T h 17 &STAT3   <ul><li>TH17 responses in mice are also  restrained byCD4+ regulatory T cells (Tregs)   </li...
STAT3  REGULATION  of CYTOKINE-MEDIATED GENERATION of TH  17 <ul><li>IL-6 functions to up-regulate IL-23R and that IL-23 s...
 
Proinflammatory  Effects  of  IL17
Stat3 links activated keratinocytes and immunocytes required for development of psoriasis   <ul><li>Epidermal keratinocyte...
<ul><li>Blocking the function of   STAT3   using antisense oligo-nucleotides inhibited the onset of, and reversed, establi...
New Informations
 
Do Other Therapies Work Within This Framework? <ul><li>Anti–T-cell agents could affect Th17 cells as  they would other T c...
Studies on Stat 3 in Psoriasis
Stat 3 in Psoriasis
 
 
New Prospectives &Directions
 
Manipulation of Psorasis
 
Therapeutic  Targets  ( Fitch   et al ,  Current Rheumatology Reports  2007,  9: 461–467 )   Fitch et al.
Message Home
Message Home <ul><li>Stat3  is Key intracellular signaling molecule important  in Th17 development and mediates IL-22–indu...
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Stat3 protein & thelper 17 cell in psoriasis

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Transcript of "Stat3 protein & thelper 17 cell in psoriasis"

  1. 1. Signal Transducer &Activator of Transcription( STAT)-3 & T Helper (Th) 17 Cell in Psoriasis <ul><li>DR M.YOUSRY ABDEL-MAWLA,MD </li></ul><ul><li>ZAGAZIG FACULTY OF MEDICINE,EGYPT </li></ul>
  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. 5. 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>
  4. 6. 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>
  5. 7. Psoriasis
  6. 8. 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>
  7. 9. Psoriasis Clinical Presentation
  8. 10. Psoriasis as an immune disorder
  9. 11. Prepsoriasis State
  10. 12. Prepsoriasis State
  11. 13. Development of Psoriasis
  12. 14. Immunopathology of Psoriasis
  13. 15. T-Cell in Psoriasis
  14. 16. 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>
  15. 17. <ul><li>Psoriasis shares immunologic and genetic features with other human autoimmune inflammatory conditions such as inflammatory bowel disease, rheumatoid arthritis, and multiple sclerosis. </li></ul><ul><li>Novel CD4 T-helper (Th) cells, called Th17 cells, are important in the pathogenesis of psoriasis. </li></ul>
  16. 18. T helper cell precursors being skewed towards Th1, Th2, Th17 and T regulatory cell (Treg) phenotypes on the basis of the cytokine environment . 
  17. 19. 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 </li></ul><ul><li>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. </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 et al. Current Rheumatology Reports 2007, 9:461–467) </li></ul>
  18. 20. PSORIASIS IS A Th17 DISEASE <ul><li>T helper (Th) 17 cells, a novel T-cell subset, have been implicated in the pathogenesis of psoriasis and other autoimmune inflammatory diseases. </li></ul><ul><li>Interleukin (IL)-23 stimulates survival and proliferation of Th17 cells, and thus serves as a key master cytokine regulator for these diseases. </li></ul><ul><li>In psoriasis, IL-23 is overproduced by dendritic cells and keratinocytes, and this cytokine stimulates Th17 cells within dermis to make IL-17A and IL-22. IL-22, in particular, drives keratinocyte hyperproliferation in psoriasis. </li></ul><ul><li>Future targeting of these key cytokines is likely to lead to dramatic clinical improvement in patients with psoriasis. </li></ul>
  19. 22. Microbial Antigens & Th 17 Response <ul><li>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   </li></ul>
  20. 23. ACTIVATION of T h 17 &STAT3 <ul><li>TH17 responses in mice are also restrained byCD4+ regulatory T cells (Tregs) </li></ul><ul><li>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.  </li></ul><ul><li>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 ) . </li></ul>
  21. 24. 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 ). </li></ul>
  22. 26. Proinflammatory Effects of IL17
  23. 27. 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. Thus, targeting Stat3 may be potentially therapeutic in the treatment of psoriasis. </li></ul>
  24. 28. <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>
  25. 29. New Informations
  26. 31. 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 Th17 cells or work directly on keratinocyte responses </li></ul>
  27. 32. Studies on Stat 3 in Psoriasis
  28. 33. Stat 3 in Psoriasis
  29. 36. New Prospectives &Directions
  30. 38. Manipulation of Psorasis
  31. 40. Therapeutic Targets ( Fitch et al , Current Rheumatology Reports 2007, 9: 461–467 ) Fitch et al.
  32. 41. Message Home
  33. 42. 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>
  34. 43. THANK YOU
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