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
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).
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 et al. Current Rheumatology Reports 2007, 9:461–467)
T helper (Th) 17 cells, a novel T-cell subset, have been implicated in the pathogenesis of psoriasis and other autoimmune inflammatory diseases.
Interleukin (IL)-23 stimulates survival and proliferation of Th17 cells, and thus serves as a key master cytokine regulator for these diseases.
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.
Future targeting of these key cytokines is likely to lead to dramatic clinical improvement in patients with psoriasis.
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 ).
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 ) )
A positive feedback mechanism for Th1/Th17 inflammation .
Th1 cells, but,not Th2 cells, produce an endogenous ligand for Toll-like receptor (TLR) 4, namely extradomain A+ fibronectin containing extra type III domain A (FnEDA+).
As TLR4 stimulation leads to production of proinflammatory cytokines that recruit (via altered endothelial adhesion molecule expression and chemokine production) more Th1/Th17 cells, a positive feedback mechanism for Th1/Th17 inflammation exists .
FnEDA+ positive feedback loops are a potential driver of Th1/Th17 in flammation (John P. McFadden et al Clinics in Dermatology (2011) 29, 257–265).
Skin trauma is one of the best-known stimuli for psoriasis plaque formation (the Koebner phenomenon).
After wound injury, TGF-β upregulates FnEDA+ and α5β1 integrin expres-macrophages) stimulation by FnEDA+ can lead to production of IL-1β, TNF-α, IL-6, IL-12, and IL-23.
These cytokines will in turn lead to endothelial expression of intercellular adhesion molecule-1, E-selectin, and vascular cellular adhesion molecule-1, with augmentation of T-cell recruitment into the lesional skin.
Such cytokine produc- tion should lead to promotion of Th1 and Th17 cell activation; and psoriasis is indeed characterized by such a cytokine and T-cell profile.
FnEDA+ will cause keratinocytes from psoriatic individuals (but not nonpsoriatic) to proliferate.
Hyperprolifer-ating keratinocytes produce proliferative keratins such as keratins 6, 16, and 17.
The observation of close homology between proliferative keratin and streptococcal M protein31 lead to the proposal that T cells that recognize epitopes in both proteins are involved in an autoimmune reaction in psoriasis.
Such an autoimmune reaction will lead to proinflammatory cytokine release, which in turn will lead to recruitment of Th1 and Th17 cells. Th1 cells will produce FnEDA+, completing the positive feedback loop.
It remains to be established whether T cells within psoriasis lesions react to keratin, so the a utoimmune loop remains as a hypothetic possibility,
Multiple genes/candidate genes variants have been associated with psoriasis.
Many of these genes can be accommodated onto a model of psoriasis based on multiple FnEDA+ loops .
Multiple FnEDA+ loops are operative in psoriasis and override regulatory attempts to switch off cutaneous inflammation, which may explain why psoriatic inflammatory plaques have the potential to persist indefinitely.