atopic dermatitis ( ad ) is a common skin disease manifested clinically by chronic inflammation and characterized histologically by skin infiltration of inflammatory cells including predominantly lymphocytes , eosinophils , and mast cells .
it affects 1020% of children and 13% of adults in developed countries , and the prevalence is increasing .
many of these patients also suffer from asthma and allergic rhinitis along with intense itching and skin infection .
although the pathogenesis and etiology of ad remain to be completely understood , this multifactorial disease likely results from a complex crosstalk between genetic and environmental factors .
exaggerated th2 response , disruption of the epidermis barrier functions , high levels of serum ige , and decreased production of antimicrobial peptides ( amps ) are the key findings in ad .
data from human and animal studies indicate that ad is a th2 dominant inflammatory skin disease at the acute stage followed by th1 involvement at the chronic stage of the disease .
specifically , this notion of th2-dominance in ad is validated by a mouse model we have successfully generated through overexpressing il-4 , a key th2 cytokine , in the basal epidermis using a epidermis - specific keratin 14 promoter .
the il-4 transgenic ( tg ) mice spontaneously develop skin lesions , serological abnormalities , and skin infection , which fulfil the clinical and histological diagnostic criteria for human ad .
consistent with an inflammatory disease process , upregulation of chemokines , proinflammatory cytokines , b cell activation molecules , angiogenic factors , and several critical adhesion molecules has been found in these tg mice . the jak - stat pathway is a classical signal transduction pathway for numerous cytokines and growth factors .
the binding of ligands to their receptors leads to jak activation , which in turn phosphorylates and activates stats .
the jak family includes jak1 , jak2 , jak3 , and tyk2 , and the stat family includes stat1 , stat2 , stat3 , stat5a / b , and stat6 . as a negative regulator of the jak - stat pathway , the socs family consists of cytokine - inducible sh2 domain - containing protein ( cis ) and socs17 .
socss may act on the activation loop of jaks , or they may interact with phosphotyrosines in the cytoplasmic domain of cytokine receptors , suppressing the jak - stat pathway with a negative feedback mechanism . in this review , we will discuss the roles that the jak - stat pathway plays in the pathophysiology of ad .
since ad is a th2-dominant disease , examination of how the jak - stat pathway regulates th2 differentiation would help us to understand the possible roles that jak - stat play in ad .
it is well established that il-4 promotes the differentiation of th2 cells , which in turn produce il-4 , il-5 , il-10 , and il-13 .
the study of il-4 and the il-4 receptor -null mice demonstrated clearly that il-4 is required for a th2 response and the production of th2 cytokines .
in addition , studies from the il-4 tg mice demonstrated upregulation of the th2 cytokines .
consistently , the il-4 tg mice generated on a th2-dominant strain , balb / c mice , develop earlier onset and worse ad - like skin lesions than the il-4 tg mice generated on a th1-dominant strain , c57bl/6 mice , suggesting that the th2 systemic immune milieu , in addition to cutaneous th2 immune milieu , plays an essential role in the pathogenesis of ad . additionally , knocking out bcl-6
, a transcription factor functioning to regulate il-4 signal transduction , leads to th2-mediated hyperimmune response in many organs , further supporting the regulatory function of il-4 on th2 immunity .
importantly , il-4 signals through the jaks - stat6 pathway to regulate th2-related target genes in lymphocytes , firmly supporting a role of jak - stat in th2 regulation .
thymic stromal lymphopoietin ( tslp ) , known to promote th2 differentiation , to activate natural killer t cells and basophils , and to affect b cell maturation , has been reported to be associated with ad . while the murine tslp receptor signals via stat3 , stat5/tec , a src type kinase , the human tslp receptor activates stat1 , stat3 , stat5/jak1 , and jak2 .
it has been reported that histamine enhances the secretion of th2 cytokines such as il-4 , il-5 , il-10 , and il-13 and inhibits the production of th1 cytokines .
histamine was shown to stimulate il-13 production through the jak - stat pathway in a murine th2 cell line .
in addition , tyrphostin , a jak - stat pathway inhibitor , reversed the effects of histamine on ifn , il-5 , and il-10 production .
horr et al . have shown that histamine , by acting through the h4 receptors on t cells , can suppress stat1 activation and help to drive the th2 response , leading to the development of ad .
it is generally accepted that tyk2 , jak2 , and stat4 , which are il-12 signaling pathway components , are essential for th1 cell differentiation , while jak1 , jak3 , and stat6 , which are il-4 signaling components , are critical for th2 differentiation .
in addition , stat5a / b , which are involved in the upregulation of gata3 and il-4r , and stat3 , which helps stat6 bind to its target genes , also play some roles in th2 cell differentiation .
stat6 regulates genes involved in th2 and b cell differentiation , ige class switching , and mhc class ii production . while stat4 null mice fail to generate th1 cells and conditional stat3 knockout mice have an exaggerated th1 response , stat6 null mice have impaired th2 cell development and ige class switching . on the contrary ,
mice expressing constitutively active stat6 ( stat6vt ) develop an ad - like skin lesion .
in addition , several stat6 polymorphisms are also associated with a predisposition to allergic diseases and high levels of ige .
a jak3 mutation in severe combined immunodeficiency ( scid ) patients leads to the absence of t cells and natural killer cells and the production of dysfunctional b cells .
a loss - of - function mutation in tyk2 leads to defects in multiple cytokine signaling pathways including type i ifn , il-6 , and il-12 .
these patients showed impaired th1 differentiation and accelerated th2 differentiation with clinical manifestations including unusual susceptibility to various microorganism infections , ad - like skin lesions , and high serum ige levels , suggesting a regulatory role of the jak family in th2 differentiation .
another tyk2 null mutation and hypomorphic mutations in stat3 are associated with the hyper - ige syndrome ( hies ) , a primary immunodeficiency characterized by ad like - skin lesions , susceptibility to infections , and high serum ige levels . in this syndrome ,
il-12 and ifn/ signal pathways are defective , thus blocking the th1 differentiation . as a result , the th2 response is exaggerated , leading to similar clinical findings as ad . because stat3 is important for b cell proliferation and differentiation ,
hies patients have decreased number of memory b cells as compared with ad patients . as a negative regulator of the jak - stat pathway , suppressor of cytokine signaling 2 ( socs2 ) deletion leads to increased susceptibility to ad as compared with wild - type mice .
these mice show an exaggerated th2 response along with significantly elevated serum ige levels , eosinophilia and low il-17 levels .
socs2-knockout cd4 t cells display constitutively high levels of stat6 phosphorylation as compared with wild type t cells .
in addition , il-2-induced stat5 activation , also involved in the early th2 differentiation , is exaggerated in the socs2-knockout cd4 t cells . on the other hand ,
il-12-stimulated stat4 phosphorylation is unaffected , and il-6 mediated stat3 phosphorylation is inhibited . since it is generally accepted that the development of the th1 , th2 , and th17 immune responses are mediated by stat4/stat1 , stat6/stat5 , and stat3 respectively , the increased stat6/stat5 activation and suppressed stat3 activation naturally lead to an exaggerated th2 response at the expense of th17 .
another example of the jak family involvement in th2 immunity is shown in nc / nga mice that develop ad - like skin inflammation .
nakagawa et al . reported that pyridone 6 ( p6 ) , a pan - jak inhibitor , delayeded the onset and reduced the severity of ad - like skin lesions in nc / nga mice .
p6 suppressed the ifn-/stat1 , il-2/stat5 , and il-4/stat6 signaling pathways strongly while it suppressed il-6/stat3 pathway only modestly , resulting in reduction of the th1 and th2 responses but the enhancement of the t17 response .
eosinophil skin infiltration is frequently observed in the skin lesions of ad patients and ad mouse models .
although stat6 null mice have defects in th2 differentiation and ige class switching , crossing these mice with nc / nga mice can not prevent the development of ad - like skin lesions .
even though these mice do not produce ige and th2 cytokines , the histological features of their skin lesions are similar to that of ad .
these authors suggested that a th2 response is not absolutely necessary for the development of ad - like skin lesions ; instead , ifn-  and eosinophil skin infiltration may play an essential role .
eosinophils express the il-31 receptor a ( il-31ra ) , and il-31 has the ability to delay the apoptosis of eosinophils and to stimulate the secretion of pro - inflammatory cytokines and chemokines through jak - stat .
in addition , il-5 , mainly involved in b cell proliferation and differentiation , was shown to induce eosinophilia when upregulated . conversely il-5 or il-5 receptor  chain ( il-5r )
il-5 signals through the jak2-stat1/stat5 and map kinases pathways to regulate genes involved in cell proliferation , survival and effector functions .
in the skin , regulatory t cells ( tregs ) help to regulate the immune response , and in ad , treg function is suppressed . depleting treg cells significantly increased the severity of the skin inflammation in ova - sensitized mice . in t cells , il-4-activated stat6 upregulates gata3 , the master regulator of th2 cells .
in addition , stat5a / b and stat3 may also play important roles in the regulation of foxp3 . on the other hand
it was reported that the ifn- gene transfer stimulates treg related cytokines and improves ad - like symptoms of nc / nga mice .
this finding , however , seems to contradict the notion that ifn-  is a promoting factor for ad . on the clinical level , treatment with a low - dose cyclosporine a
is effective in reducing skin inflammation with simultaneous increase of treg population in ad patients , further supporting a role of treg in ad .
stat3 , mediating the il-23 and il-6 pathways , is critical for the differentiation of th17 cell . in the early stage of human ad ,
the number of th17 cells is increased , and il-17 has been reported to upregulate adhesion molecules on keratinocytes , enhancing t cell - keratinocyte adhesion and t cell - mediated cytotoxicity . however , in chronic ad , the th17 pathway is suppressed , which could account for the amp deficiency in ad .
in the skin lesions of ad patients as well as ad mouse models , the number of mast cells is increased .
il-9 stimulates vegf production from human mast cells through the activation of stat3 in an in vitro experiment .
interestingly , il-9 serum levels in ad patients are not different from those of non - ad controls even though il-9 and its receptors are upregulated in the lesional skin of the ad patients , suggesting that the upregulation of vegf in mast cells via il-9 may be a localized cutaneous phenomenon .
the prominent increase of mast cell vegf production and angiogenesis in an ad animal model also supports the role of jak - stat in this immune pathway
being a major cell type of the skin and possessing the ability to participate in various immune responses , epidermal keratinocytes are likely an active player in the skin inflammation of ad .
we and others have shown that the dysregulation of the keratinocyte genes by il-4 play an important role in ad .
the type i receptor consisting of il-4r and il-2rc chains is expressed in hematopoietic cells , while the type ii receptor consisting of il-4r and il-13r1 is expressed in other cell types including keratinocytes . in keratinocytes , both il-4 and il-13 binds to il-4r and il-13r1 .
il-13r2 , which was reported as a dominant negative inhibitor for both il-4 and il-13 , binds to il-13 with high affinity , but lacks a significant cytoplasmic domain .
we have previously reported that il-13r2 is upregulated by il-4 in keratinocytes . in ad patients
this may be due to a negative feedback mechanism available to keratinocytes to maintain homeostasis .
we have also shown that il-4 upregulates chemokines ccl8 , ccl24 , ccl25 , ccl26 , ccl3l1 , cxcl6 , and cxcl16 , all known for their roles in the pathophyisology of ad .
the eotaxin subfamily that consists of ccl11/eotaxin-1 , ccl24/eotaxin-2 , and ccl26/eotaxin-3 plays an important role in ad .
cysteine receptor 3 ( ccr3 ) , which are expressed predominantly on eosinophils , recruiting these cells to the inflammatory site .
skin infiltrating eosinophils release a variety of cytotoxic granule proteins to cause tissue damage . in the regulation of ccl26 , though both stat3 and stat6 are phosphorylated by il-4 , only stat6 is functionally activated .
detailed analysis of the promoter of the ccl26 gene has shown that the stat6 response element consists of two palindromic half sites ttc and gaa spaced by four nucleotides .
others also reported that stat6 , different from other stat members , prefers the stat sites with four spacing nucleotides .
in addition to tyrosine phosphorylation , stat3 activation may also involve serine phosphorylation and lysine acetylation .
knockout mice studies indirectly support our results in that while stat6 null mice demonstrated defects in eosinophil tissue infiltration , the stat3 cre - loxp knockout mice did not show similar defects .
furthermore , il-4 and il-13 double knockout mice , when sensitized with ovalbumin , develop a skin lesion characterized by intact cd4 dermal infiltration , severely diminished eosinophil infiltration , and undetectable ova - specific ige levels , suggesting that stat6 activation is required for eosinophil skin infiltration in ad .
in addition to chemokines , il-4 also upregulates pro - inflammatory factors , such as il-1 , il-19 , il-20 , il-25 , il-27 , il-12r2 , il31ra , and nitric oxide synthase 2 ( nos2 ) .
moreover , we demonstrated that il-4 signals through the jak - stat pathway to regulate il-19 expression in keratinocytes .
using pcr array , we have found that that il-4 upregulates angiogenic or lymphangiogenic - related genes , such as vegf , ang-1 , angl-4 , igf1 , notch4 , pgf , and mcp-1 .
using the il-4 tg mice and cell culture , we showed that cd11b macrophages attracted to the skin lesion by mcp-1 may account for lymphangiogenesis observed in ad by secreting vegf - c .
while il-4 upregulates chemokines , pro - inflammatory factors , angiogenic factors in keratinocytes , it downregulates antimicrobial peptides ( amps ) or factors involved in apm production .
other groups have also demonstrated that the dysregulation of amps affects the development of ad .
human -defensin-3 ( hbd-3 ) , which is significantly decreased in ad , is downregulated by il-4 , il-10 , and il-13 .
in addition , hbd-2 and human cathelicidin ( ll-37 ) were also found to be reduced in ad skin lesions as compared with psoriasis .
suggested that low levels of ll-37 suppressed by il-4 and il-13 through stat6 may be the mechanism responsible for increased vaccinia virus replication as occurred in eczema vaccinatum of ad patients .
skin barrier function defects are critical for the development of ad . in addition to the filaggrin mutations in some ad patients , cytokines
they are downregulated by il-4 and il-13 in keratinocytes , and in stat6 transgenic mice , their expression is significantly decreased as well . in addition ,
filaggrin , which is reduced in acute ad skin lesion , is also suppressed by il-4 and il-13 in keratinocytes .
interestingly , while il-4 markedly reduces ceramide levels in the epidermis by downregulating the expression of serine - palmitoyl transferase-2 , acid sphingomyelinase , and -glucocerebrosidase , th1 cytokines ( gm - csf / ifn-/tnf- ) increase the ceramide levels .
taken together , the role that il-4 plays in the dysregulation of keratincoyte functions in ad involves the upregulation of chemokines , pro - inflammatory factors , and pro - angiogenic factors and the downregulation of amps and factors responsible for skin barrier function .
pruritis in ad is induced by complicated crosstalks among keratinocytes , immune cells , and nerve fibers .
the data from the nc / nga mice studies indicate that although il-4 is a key mediator of the inflammatory process in ad , il-31 might be the key causative factor for pruitus .
in addition , il-31 transgenic mice developed a th2 immune response with severe pruritic skin lesions similar to ad .
il-31 is upregulated in the skin of ad patients , and it induces the itching sensation either by direct stimulation of the dorsal root ganglion fibers that express il-31ra or by indirect stimulation of pruritic factors from keratinocytes .
il-31 receptor activation in keratinocytes induces calcium influx and stat3 mediated -endorphin production , which may contribute to the peripheral itching in ad .
thus far , data from our laboratory and others seem to indicate an influential role of jak - stat in the pathogenesis of ad , with il-4 being a key mediator ( figs . 1 and 2 ) .
specifically , the jak - stat pathway is instrumental for the th2 cell differentiation . in the immune milieu of ad ,
the enhancement of th2 cell proliferation and their release of various cytokines via the jak - stat pathway is likely the critical factor for the inflammatory responses in ad .
this th2 immune upregulation could then lead to b cell maturation and plasma cell differentiation , resulting in the hyper - secretion of ige .
similarly , this hyper th2 immune milieu triggers epidermal cells to release various chemokines , pro - inflammatory cytokines , and angiogenic factors that participate in ad pathophysiology .
moreover , il-5 released from this hyper th2 milieu could activate eosinophils that are attracted to the skin by the eotaxin subfamily , further worsening the ad condition .
in addition , by way of il-31 , an inducer of pruritus , ad becomes increasingly intensified . figure  1 . proposed mechanism of jak - stat involvement in atopic dermatitis ( ad ) development , part
in addition to the filaggrin gene mutation defects in some ad patients , il-4 is also able to downregulate barrier proteins filaggrin , loricrin and involucrin through the jak - stat pathway making the epidermis more penetrable by allergens and pathogens .
once penetrated through the epidermis , allergens / pathogens are detected by dendritic cells , which become subsequently activated to present these antigens to nave th0 cells .
the th0 cell can then differentiate into the th2 cell through the jak1,3-stat6 pathway under the influence of il-4 .
in the th0 cells , the stat6 pathway can also upregulate gata3 , a master regulator of th2 cells .
gata3 in turn suppresses foxp3 , the master regulator in treg cells , thus allowing more t cells to be activated .
proposed mechanism of jak - stat involvement in atopic dermatitis ( ad ) development , part ii . here
, th2 cells play a significant role . by their abilities to provide il-4 and il-5 stimulation via the jak - stat pathway , immature b cells could be differentiated into mature b cell and plasma cells would undergo antibody heavy chain switching to ige class .
the subsequent binding of ige to skin mast cells could lead to release of histamine , which is known to exacerbate ad .
similarly , this hyper th2 immune milieu , particularly il-4 , could trigger epidermal cells to produce and release various chemokines ( such as ccl26 ) , pro - inflammatory cytokines , and angiogenic factors , leading to ad pathophysiology .
moreover , il-5 released from this hyper th2 milieu could , through jak - stat pathway , activate eosinophils , and attract them to the skin via ccl26 , further worsening the ad condition .
in addition , by way of il-31 , an inducer of pruritus , ad symptoms could become increasingly intensified .
our understanding of the jak - stat pathway and its relationship to the dysregulated immune response and keratinocyte function is still in its infancy .
what exact roles do the different jaks and stats play in the pathogenesis of ad ? answering these questions will enable us to target more specifically the key components of the complex pathophysiology of ad , thus providing the best treatment for this disease .
 atopic dermatitis ( ad ) , a common chronic inflammatory skin disease , is characterized by inflammatory cell skin infiltration . 
 the jak - stat pathway has been shown to play an essential role in the dysregulation of immune responses in ad , including the exaggeration of th2 cell response , the activation of eosinophils , the maturation of b cells , and the suppression of regulatory t cells ( tregs ) . 
 in addition , the jak - stat pathway , activated by il-4 , also plays a critical role in the pathogenesis of ad by upregulating epidermal chemokines , pro - inflammatroy cytokines , and pro - angiogenic factors as well as by downregulating antimicrobial peptides ( amps ) and factors responsible for skin barrier function . in this review 
 , we will highlight the recent advances in our understanding of the jak - stat pathway in the pathogenesis of ad . 
Introduction
JAK-STAT in Th2 Differentiation
JAK-STAT in Eosinophils
JAK-STAT in Tregs
JAK-STAT in Th17 Cells
JAK-STAT in Mast Cells
JAK-STAT in Epidermal Keratinocytes
Conclusion