ms is a chronic progressive cns inflammatory disease , in which the autoimmune response against the cns myelin proteins leads to a chronic inflammatory response [ 1 , 2 ] .   during the inflammatory response ,
autoreactive t - cells migrate through the otherwise impermeable blood - brain barrier into the cns perivascular areas , where they cause demyelination and axonal degeneration .  
the chronic inflammatory response leads to neuronal conduction deficits associated with neurological symptoms and eventually results in the loss of functional neuronal tissue .   several immunomodulatory and immunosuppressive therapies ( ifn
, glatiramer acetate , fingolimod , natalizumab , and mitoxantrone ) are used in clinical practice as effective therapies in controlling disease activity and disability progression in patients with rr ms .   
th17-cells have been shown to play a critical role in the development of autoimmune responses in several autoimmune diseases , including ms , rheumatoid arthritis , psoriasis , juvenile diabetes , ulcerative colitis , and autoimmune uveitis [ 3 , 4 ] .  
th17-cells are identified in the cns ms lesions , cerebrospinal fluid , and among the blood - derived mononuclear cells from ms patients , implying that they may play a critical role in the immunopathogenesis of ms [ 58 ] .  
our laboratory has identified increased numbers of th17-cells and an increase in the th17-cells ' master regulatory transcription factor , retinoic acid - related orphan nuclear factor ( rorc ) , and cytokines that mediate th17-cell expansion   in ms lesions .  
th17-cell frequency is approximately 7 times higher in the peripheral circulation of rr ms patients in comparison to healthy controls ( hcs ) , and it positively correlates with the clinical disease activity .   while multiple studies have reported on the association of th17-cells and autoimmune diseases , only several reports have provided a mechanistic data on the function of il-17a in the development of the autoimmune response .   
il-17a induces the secretion of cxcl1 and cxcl2 , neutrophil - attracting cytokines , which attract those inflammatory cells into the cns in the early or acute phase of the disease .   il-17a
together with il-22 induces blood brain barrier permeability due to their effect on the endothelial cells .  
il-17a induces production of additional proinflammatory cytokines , including il-1 and il-6 , and cytokines coexpressed by th17-cells , il-9 , il-21 , il-22 , and gm - csf , also contribute to the development of the autoimmune response .  
socs proteins are a family of intracellular cytokine - inducible proteins , consisting of 8 members ( cis and socs1-socs7 ) .  
they have two structural components : an src homology domain ( sh2 ) , which is involved in phosphotyrosine binding to activated signaling molecules and a c - terminal socs box involved in the degradation of signaling molecules through the ubiquitin - proteasome pathway .  
socs gene expression is triggered by interleukins , interferons , haematopoietic growth factors , and tlr ligands such as lipopolysaccharides ( lps ) and cpg - containing dna [ 13 , 14 ] .  
the induction of the socs proteins occurs through cytokine - mediated activation of the janus kinase / signal transducers and activators of the transcription ( jak / stat ) signaling pathway , which leads to the phosphorylation of the stat transcription factors .  
the socs proteins negatively regulate cytokine signaling through their association with phosphorylated tyrosine residues on jak proteins and/or cytokine receptors or by inhibition of stat binding to the cytoplasmic domain of the receptors .  
they terminate the inflammatory responses by mediating proteasomal degradation of the bound proteins [ 13 , 15 , 16 ] .   among the socs family members ,
socs1 and socs3 have been described to play the most important role in the regulation of the autoimmune response .  
they block phosphorylation - dependent activation of stat1 in response to ifn- , or stat3 in response to il-6 , and target the ifnr- and il-6r - signaling complexes for proteasomal degradation .  
interestingly , two recent large genetic studies have identified socs1 as one of the genes with the strongest association with the susceptibility for ms [ 18 , 19 ] . among the available ms therapies , ifn and the recently introduced statins
have been reported to exert their immunomodulatory effects through the induction of socs1 and socs3 in various inflammatory cell subsets .  
ifn and statins inhibit th17-cell differentiation directly and indirectly via their effects on antigen - presenting cells ( apcs ) .   in this paper , we will discuss their therapeutic effects in rr ms patients , which are indirectly mediated through the induction of socs1 and socs3 in monocytes , dcs , and b - cells as well as directly affecting the th17-cells .
similar to th1- and th2-cells , the differentiation of th17-cells is orchestrated by cytokines secreted by apcs .
the differentiation of mouse and human th1-cells occurs upon exposure to il-12 and ifn- and th2-cells upon exposure to il-4 and il-10 , whereas the differentiation of mouse and human th17-cells differ in the required th17-polarizing cytokines [ 20 , 21 ] .  
tgf- and il-6 are required in the mouse , while il-6 , il-1 , and il-23 drive human th17-cell differentiation [ 2224 ] .  
specific stat molecules are involved in the differentiation of each t - cell subset .  
th1-cells ' differentiation induced by ifn- and il-12 mediate activation of stat4 and stat1 , which directly control the transcription factor t - bet .   in the differentiation of th2-cells ,
il-4-induced stat6 phosphorylation is crucial for the gene transcription of the master regulatory transcription factor gata-3 , whereas stat3 is pivotal in human and mouse th17-cell differentiation , where it is induced by il-6 , il-23 , and il-21 .  
these studies have demonstrated a pivotal role of stat molecules in t - cell differentiation .  
stats ' regulation is critical for the cytokine secretion profile and the subsequent inflammatory t - cell responses .
socs1 is induced by various cytokines , including ifn , ifn , il-4 , and il-6 [ 27 , 28 ] , which activate the jak / stat signaling pathway .  
several studies have demonstrated that socs1 is induced by the tlr4 ( lps ) and tlr9 ligands ( cpg - dna ) [ 14 , 29 ] .  
socs1 classically inhibits ifn signaling through association with the ifn- receptor 1 ( ifnar1 ) and ifn- receptor ( ifngr ) subunits and suppression of ifn - induced stat1 and stat3 phosphorylation [ 3032 ] .  
in addition to ifn regulation , socs1 also inhibits tnf- signaling [ 14 , 29 ] .  
socs1 deficiency leads to overresponsiveness to ifn- , whereas socs1 overexpression leads to a reduced responsiveness to ifn- in various cell subsets [ 31 , 33 , 34 ] , implying that socs1 plays a negative regulatory role in ifn- signaling .
socs3 is expressed in dcs , monocytes , t - cells and b - cells upon induction by il-2 , il-3 , il-6 , il-12 , il-23 , ifn// , il-27 , il-4 , il-10 , il-1 , tgf , tnf- , gm - csf , and lps .  
socs3 expression is high in resting cd4 cells , but it rapidly decreases after t - cell receptor activation .  
earlier studies have reported that during t - cell differentiation , socs3 is selectively expressed in th2-cells , while socs1 expression is higher in th1-cells .  
high socs3 expression in transgenic mice led to skewing to th2 type differentiation , because socs3 binds to il-12rb2 and inhibits the il-12-mediated stat4 activation , therefore blocking th1-cell development .  
socs3 inhibits il-6 signaling by binding to the il-6 gp130 receptor complex and mediating its proteasomal degradation [ 36 , 37 ] .  
, stat3 induces the expression of the master regulatory transcription factor rorc and is , therefore , critical for the differentiation of human and mouse th17-cells [ 26 , 38 , 39 ] .  
a socs3 deficiency in nave t - cells leads to a sustained stat3 phosphorylation and results in higher frequencies of differentiated th17-cells .  
in addition , socs3 deficiency in t - cells is associated with enhanced il-17a production , induced by il-23 or il-6 plus tgf- .  
il-27 signaling can also induce socs3 via stat1 so that il-27 may block th17-cell development , as may type i and ii ifns , via sequential activation of stat1 and socs3 , resulting in stat3 antagonism .  
monocytes , cd4 and cd8 t - cells were found to have a lower socs3 and increased stat3 expression during ms relapses .  
furthermore , socs3 suppresses the th17-polarizing cytokine il-1 and il-23 secretion by dcs and b - cells [ 43 , 44 ] .  
socs3 is induced by several stimuli in apcs , where it plays an important role in the inhibition of th17 polarizing cytokines il-1 and il-23 , which suppress stat3 activation required for the gene transcription of the master th17 cell regulatory transcription factor rorc .
these studies suggest that socs3 induction may represent a beneficial therapeutic approach in patients with rr ms .
ifn is an innate immune response cytokine that suppresses the disease activity and disability progression of rr ms and its animal model , experimental autoimmune encephalomyelitis ( eae ) .  
earlier studies in mice and humans have demonstrated an association between an endogenous ifn deficiency and an increased susceptibility for eae and rr ms [ 45 , 46 ] .   
in addition , the administration of exogenous ifn effectively reduced the clinical relapse rate and the formation of new cns lesions in several large placebo - controlled clinical trials .  
an increase in the th1 receptor il-12r2 expression and the secretion of the immunoregulatory cytokine il-10 [ 48 , 49 ] were identified as the biomarkers of ifn 's therapeutic effects .  
multiple proposed mechanisms of ifn 's therapeutic effect include inhibition of antigen presentation , suppression of t - cell proliferation and migration , and modulation of proinflammatory cytokine production [ 48 , 49 ] .  
more recent studies have shown that ifn effectively suppresses th17-cells differentiation in mouse and human .  
mice deficient for ifnar1 receptor and its downstream signaling molecules have been found to be more susceptible to eae [ 50 , 51 ] .  
in addition , durelli et al . have demonstrated that ifn reduced the numbers of th17-cells in their longitudinal study of ifn-1a - treated rr ms patients .  
this finding has been supported by our in   vitro experiments on the effect of ifn on human th17-cell differentiation , where we demonstrated that ifn suppresses th17-cell differentiation via its effects on monocytes , dcs , b - cells and nave t - cells [ 43 , 44 , 52 ] .  
monocytes , macrophages , dcs and b - cells induce human th17-cell differentiation through their secretion of il-1 and il-23 .  
have reported an increased expression of il-23p19 in acute ms brain lesions , while vaknin - dembinsky et al .
identified an increased synthesis of il-23 by dcs derived from ms patients [ 53 , 54 ] .  
in our in   vitro experiments , we found a decreased expression of il-1 and il-23 , whereas il-12p35 and il-27 gene expression was increased in ifn-treated dcs .  
rr ms patients treated with ifn have been reported to have reduced il-23p19 gene expression in their peripheral blood mononuclear cells ( pbmcs ) , a finding that is reinforced by our in   vitro experiments showing that dcs and b - cells exhibited decreased il-23 secretion upon incubation with ifn [ 43 , 44 , 52 ] .  
we also demonstrated that the reduced secretion of il-1 and il-23 in supernatants ( sns ) from ifn-treated dcs led to a decreased differentiation of th17-cells .  
the addition of il-1 and il-23 and the blocking of il-27 in the sns from ifn-treated dcs and b - cells lead to a reversal of the ifn effect and an increase in th17-cell differentiation [ 43 , 44 ] .   in ifnar knock - out mice that are highly susceptible to eae , the eae is reversed with il-27 administration .  
these studies led us to conclude that ifn suppresses the th17-cell differentiation by inhibiting il-1 and il-23 and inducing il-27 secretion in dcs and b - cells as shown in figure 1 .
ifn is a potent inducer of socs1 and socs3 , molecules that contribute to th17-cell differentiation [ 43 , 55 , 56 ] .  
we observed an increased expression of socs3 in ifn-treated dcs , which is induced through stat3 activation [ 43 , 44 ] .  
several studies have reported that socs3 suppresses il-1 and il-23 expression [ 57 , 58 ] .   collectively , these reported in   vitro and in   vivo findings indicate that ifn suppresses the il-1 and il-23 expression through socs3 upregulation in dcs and b - cells [ 43 , 44 ] .  
we found that b - cells from rr ms patients and hcs exhibit an increased socs1 expression upon ifn-induced stat1 phosphorylation .   in   vivo studies by liu et al .
have demonstrated that ifn-1b treatment of rr ms patients inhibits the cd40 co - stimulatory molecule expression on b - cells .  
we further identified in our experiments that ifn   inhibited cd40 expression on b - cells through the induction of socs1 .  
stat1 inhibition with fludarabine leads to increased cd40 expression in b - cells and the reversal of ifn-1b 's in - vitro effect [ 44 , 55 ] .  
similar findings have been reported for the ifn-- and ifn--induced cd40 expression on macrophages .   in a recent study , we have demonstrated that socs1 plays an important role in the regulation of b - cell cd40 expression and subsequently on their antigen presenting capacity .  
the t - cell proliferation decreased when ifn-pretreated b - cells were used as apcs and cocultured with the antigen - specific t - cells .  
in contrast , the proliferative response was reversed when the ifn-treated b - cells were simultaneously incubated with the stat1 inhibitor fludarabine .  
these results confirm the role of ifn-1b - induced stat1 phosphorylation and socs1 expression in the inhibition of the antigen presenting capacity of b - cells .   in a recent study , tanaka et al .
have demonstrated that the eae induction was reduced in mice with a t - cell - specific socs1 knockout , which differentiated into th1-cells , while the frequency of th17-cells was reduced .  
the socs1-deficient t - cells exhibited a sustained stat1 activation .   in the absence of an socs1 inhibitory effect on ifn- signaling , nave t - cells
not all rr ms patients respond to ifn therapy , and early identification of nonresponders is important to avoid irreversible disability progression .  
have recently demonstrated that monocytes from rr ms nonresponders have an increased baseline level of stat1 phosphorylation and ifnar1 expression compared to ifn-responders , which are identified by the suppression of clinical disease activity .  
the expression of socs1 and socs3 was similar in responders and non - responders , suggesting that these negative regulators of stat1 activation may be expressed but functionally deficient in non - responders .   in summary
the induction of socs1 in b - cells leads to cd40 suppression , whereas the induction of socs3 inhibits the gene expression of th17-polarizing cytokines il-1 and il-23 .   in nave
cd45ra t - cells , ifn also induces socs3 which inhibits stat3 cell signaling and a subsequent expression of the th17-cell master regulatory transcription factor rorc .
statins are selective inhibitors of 3-hydroxy-3-methylglutaryl ( hmg)-coa reductase , an enzyme involved in the conversion of hmg - coa to mevalonic acid .  
statins have been widely used as cholesterol - lowering agents in the treatment of cardiovascular diseases .  
more recently , they have been found to have anti - inflammatory and immunomodulatory properties , since they inhibit dcs ' maturation and antigen presentation [ 62 , 63 ] .  
the anti - inflammatory benefits of statins are related to their ability to reduce mevalonate and the mevalonate - derived isoprenoids farnesyl pyrophosphate ( fpp ) and geranylgeranyl pyrophosphate ( ggpp ) .  
fpp and ggpp are involved in the posttranslational modification of small g - proteins .  
simvastatin may have a therapeutic potential in rr ms , since it has been demonstrated to decrease new cns lesion formation by 42% after six months of treatment in comparison to the baseline magnetic resonance imaging studies .  
we have also reported that nave cd45ra t - cells cultured with sns from simvastatin - treated monocytes decreased th17-cell differentiation .  
the simvastatin treatment of monocytes and dcs from rr ms patients and hc induced decreased expression of the th17-promoting cytokines il-1 and il-23 [ 66 , 67 ] .  
we have also identified an increase in the socs3 expression in simvastatin - treated monocytes [ 68 , 69 ] .  
statin - induced socs3 downregulates the expression of il-1 and il-23 , creating a cytokine milieu that inhibits the th17-cell differentiation , as shown in figure 1 .  
previous eae studies have indicated that statins shifted th1 cytokine ( ifn- , il-12 , and tnf- ) to th2 cytokine production ( il-4 , il-5 , and il-10 ) .   a more recent study has suggested that statins inhibit human th17-cells ' differentiation and the production of the th17 cytokines il-17a , il-17f , il-21 , and il-22 .  
huang et al . have demonstrated that statins block stat1 phosphorylation , which is crucial in ifn- signaling and th1-cell differentiation .  
socs3 , a negative regulator of stat1 and stat3 activation , is increased in the statin - treated cells .  
statin - induced socs3 expression is proposed to downregulate the stat1 and stat3 phosphorylation during th1 and th17-cell differentiation , through which its therapeutic effect is mediated in rr ms .
ifn and statins have been shown to be an effective treatment of rr ms .   despite different mechanisms of action , both therapies target similar signaling pathways .  
ifn suppresses the differentiation of pathogenic th17-cells , through its effect on the cells of the innate system ( macrophages , monocytes , dcs , and b - cells ) , by the inhibition of the th17-cell - promoting cytokines il-1 and il-23 via induction of socs3 .  
in b - cells , ifn downregulates cd40 costimulatory molecule expression through the induction of socs1 .  
statins lead to socs3 and socs7 expression in the innate immune response cells .   in monocytes and dcs
, socs3 inhibits il-1 and il-23 expression , which leads to an inhibitory cytokine milieu for the th17-cells ' differentiation .  
statins and ifn both induce the socs3 expression , which is crucial in the suppression of th17-cell differentiation and consequently for their therapeutic effect in rr ms .   
the available results have identified socs proteins as an attractive therapeutic target in autoimmune diseases .  
the designer socs - mimetic drugs have already been tested in an animal model of the cns inflammatory disease .  
tyrosine kinase inhibitor peptide ( tkip ) , a short peptide socs1 mimetic , both prevented and treated active eae , thus representing a promising therapeutic approach that will likely be further pursued in clinical testing .
 multiple sclerosis ( ms ) is an inflammatory demyelinating , presumably autoimmune disease of the central nervous system ( cns ) .   among the available ms therapies , interferon ( ifn) and the recently introduced statins 
 have been reported to exert their immunomodulatory effects through the induction of socs1 and socs3 in various inflammatory cell subsets . 
 the socs proteins negatively regulate cytokine and toll - like receptors- ( tlr- ) induced signaling in the inflammatory cells . 
 socs1 and socs3 have been reported to play an important role in the regulation of th17-cell differentiation through their effects on the cells of the innate and adaptive immune systems . 
 ifn and statins inhibit th17-cell differentiation directly and indirectly via induction of socs1 and socs3 expression in monocytes , dendritic cells ( dcs ) , and b - cells . due to their rapid induction and degradation , and socs - mediated regulation of multiple cytokine - signaling pathways 
 , they represent an attractive therapeutic target in the autoimmune diseases , and particularly relapsing remitting ( rr ) ms . 