immune responses against pathogens determine the course of 
 infection as well as the pathogenesis of diseases caused by the 
 pathogens . during the responses , immune cells , such as dendritic 
 cells , macrophages , and t and b lymphocytes , for 
 instance , during infections with some protozoa , such as 
 leishmania major or trypanosoma cruzi , the 
 importance of ifn- has been proven not only experimentally 
 but also clinically [ 1 , 2 ] . ifn- is produced mainly 
 by helper t cell ( th ) 1-differentiated cd4 t cells , a 
 population induced by il-12 , although other types of cells , such 
 as nk / nkt cells and cd8 t cells are also known to produce 
 ifn-. while being critically important for the defense 
 against pathogens , cytokines are sometimes notorious as causative 
 agents for the development of immunopathology and inflammation , 
 which may result in organ / tissue damage . tnf- , a cytokine 
 produced by th1-type cd4 t cells and activated macrophages 
 for defense against intracellular pathogens , may induce cell 
 apoptosis or necrosis depending on situation . therefore , it is 
 essential that one should mount proper immune responses against 
 pathogens , making sure the response is not too weak to eliminate 
 pathogens or too strong to damage the host . recently , two new 
 cytokines , il-23 and il-27 have been identified as members of the 
 il-12 cytokine family . with il-12 , a cytokine known as the most 
 potent th1-inducing cytokine , the il-12 cytokine family has been 
 shown to be involved in various diseases such as infection , 
 autoimmune diseases , and inflammations . this review will focus on 
 the complicated roles of il-27 , as well as those of related 
 cytokines , and their potential importance during some protozoan infections . when stimulated through t - cell receptors , cd4 t cells 
 proliferate and differentiate into either th1 or th2 cells , two 
 functionally distinct subsets that produce characteristic 
 cytokines , respectively . th1 cytokines , especially 
 ifn- , are critical for the macrophage activation and 
 nitric oxide production required for eliminating intracellular 
 pathogens such as l. major . in contrast , th2 cytokines such as il-4 , il-5 , and il-13 are important for inducing 
 humoral immunity required to expel helminth from the digestive 
 canal . th1 and th2 cells develop from the same th precursor ( thp or th0 ) cells , but which subset differentiates in a 
 given situation is driven by factors , particularly cytokines , in 
 the surrounding microenvironment . il-12 promotes ifn- 
 production and th1 development , whereas il-4 binding to the 
 il-4 receptor promotes il-4 production and th2 development 
 . developments of th1 and th2 are mutually exclusive and differentiation of one suppresses that of the other by various 
 mechanisms . in addition to these two subsets , recent lines of 
 evidence have shown that there is another th subset , called th17 
 or thil-17 [ 79 ] ( figure 1 ) . th17 
 cells produce il-17 for induction of various inflammatory 
 responses and for defense against some pathogens [ 10 , 11 ] . the differentiation of th17 cells requires il-6 plus tgf- for commitment and il-23 for development , while other cytokines such as il-1 and tnf- also support the development of th17 [ 1214 ] . il-12 was originally identified as a potent inducer of 
 ifn- production by t , nk , and other types of lymphocytes 
 and was shown later to be a potent inducer of th1 differentiation 
 of cd4 t cells . until recently , il-12 has been the only known heterodimeric cytokine , composed of two subunits , p35 
 and p40 . the p35 subunit is homologous to il-6 and g - csf with a 
 four--helix bundle structure , while the p40 subunit is 
 homologous to the extracellular portion of il-6r and 
 related cytokine receptors . thus , it was proposed that il-12 
 evolved from a cytokine of the il-6 family , which is 
 covalently bound to the extracellular portion of its primordial 
  chain receptor . recently , il-23 and il-27 were identified as heterodimeric cytokines functionally and 
 structurally related to il-12 [ 16 , 17 ] ( see [ 18 , 19 ] for review ) . now along with two other cytokines , clc / soluble cntfr and clc / clf-1 , il-12 , il-23 , and il-27 compose a family of 
 heterodimeric cytokines [ 18 , 20 ] . il-23 , a heterodimeric cytokine composed of the il-12p40 subunit and the il-12p35-related molecule p19 , preferentially acts on memory th1 cd4 t cells for their proliferation , although il-23 has recently been shown to promote th17 differentiation . il-27 , another 
 heterodimeric cytokine composed of the il-12p40-related protein 
 ebi-3   plus the il-12p35-related protein p28 , acts on nave cd4 t cells to induce the expression of the 
 il-12r2 gene and make the cells responsive to il-12 . while 
 il-12 is the most potent inducer of th1 differentiation and 
 ifn- production acting on effector th1 cells , 
 chronologically differential roles and differential usage of 
 il-12 , il-23 , and il-27 first , il-27 commits 
 nave cd4 t cells to differentiate into th1 cells by 
 inducing il-12r2 , then il-12 acts on committed effector 
 th1 cells for ifn- production , followed by il-23 
 mediating the proliferation of memory th1 cells   ( figure 2 ) . while the th1 immune response is pivotal for the host defense against pathogens including some bacteria and 
 parasites such as listeria monocytogenes , 
 mycobacterium tuberculosis , and l. major 
 ( reviewed by romani et al . in ) , as well as 
 against tumors , excess of th1 responses may cause some autoimmune diseases including rheumatoid arthritis and multiple 
 sclerosis [ 24 , 25 ] . it is of note that recent lines of evidence have shown that some of these  th1-mediated  autoimmune diseases are actually mediated by il-23-driven th17 cell populations but not by il-12-driven th1 cell populations , as has 
 been shown for experimental autoimmune encephalomyelitis , an 
 experimental model for multiple sclerosis [ 7 , 8 ] ( see also [ 26 , 27 ] for review ) . nonetheless , proper initiation , 
 reinforcement , and maintenance of the th1 response seems to be 
 ensured , and at the same time tightly regulated by related , but 
 distinct , cytokines . sprecher et al . cloned an orphan cytokine receptor and named it 
 wsx-1 ( what is now called il-27r  chain ; also known as 
 tccr ) after the wsxws motif , a characteristic feature of cytokine 
 receptors , in its extracytoplasmic portion . wsx-1 binds to the gp130 ( of il-6r ) to conform to a fully functional il-27 
 receptor complex , downstream of which , stat1 and stat3 are 
 activated by ligand binding [ 30 , 31 ] . although the function of 
 wsx-1 was not clear in the original cloning paper , two groups 
 including ours independently generated strains of mice with 
 wsx-1 ( or tccr ) gene disruption and demonstrated 
 that wsx-1 is critical for induction of th1 responses and 
 ifn- production . chen et al .   demonstrated that wsx-1 mice showed impaired ifn- 
 production and remarkable susceptibility to l. monocytogenes . in the report by yoshida et al . , an impairment of th1 development and ifn- production was also demonstrated in 
 wsx-1 mice infected with l. major . interestingly , impaired production of ifn- as only observed at early phases of l. major infection , and the 
 ifn- production in wsx-1 mice was restored to the wild - type level at later phases of infection . in accordance with this  in vivo  observation , t cells from 
 wsx-1 mice produced much less ifn- than wild - type cells during primary stimulation in the presence of il-12 for th1 differentiation , while fully differentiated 
 wsx-1 th1 cells produced a comparable level of ifn- upon secondary stimulation . these data , both  in vivo  and  in vitro ,  indicated that wsx-1 is required for the initial mounting of the th1 response by nave cd4 t cells , but its role is later mitigated presumably by the il-12 
 system in fully activated and differentiated th1 cells . the 
 importance of wsx-1 in th1 differentiation was further 
 substantiated by the discovery of il-27 , a ligand for wsx-1 , as 
 another th1-inducing composite cytokine . early expression of p28 , a component of il-27 , prior to that of il-12 
 components , by activated dendritic cells also supported the idea 
 that il-27 was involved in the early phase of th1 differentiation 
 . a report on the role of ebi-3 , a subunit of il-27 , in which ebi-3-deficient mice showed susceptibility to l. 
 major infection with impaired th1 response also supported the 
 importance of il-27/wsx-1 in th1 differentiation . ( see table 1 for comparison . ) while resistance against l. major exclusively depends on 
 proper th1 responses , expulsion of trichuris muris , a 
 gastrointestinal nematode from digestive canals largely depends on 
 th2 responses . in our recent t. muris infection 
 experiments [ 35 , 36 ] , wsx-1 mice successfully 
 expelled the worm and failed to harbor chronic infection in 
 contrast to wild - type mice . wsx-1 lymphocytes produced significantly less ifn- and much more il-4 and il-13 than wild - type cells in response to the worm antigen , 
 reiterating that wsx-1 is important for the initial mounting of 
 proper th1 responses during infection . another interpretation of 
 the results , however , is also possible for the impairment of th1 
 responses against l. major and t. muris 
 infection . stat1 was shown to bind to the cytoplasmic portion of wsx-1 in a tyrosine 
 phosphorylation - dependent manner and following stat1 activation by 
 il-27 stimulation , t - bet was activated to promote th1 
 differentiation . the binding of stat1 to wsx-1 is reasonable , 
 since wsx-1 has pyekhf motif at the conserved tyrosine residue , 
 which shares amino acid similarities to the stat1 docking site of 
 the ifn-r , pydkph [ 38 , 39 ] . stat1 activation per se 
 by il-27 stimulation has no direct effect on ifn- 
 production but stat1-mediated t - bet activation followed by 
 il-12r2 expression was one of the critical events for th1 
 differentiation . other mechanisms , such as mhc class i 
 augmentation , icam-1 expression , and suppression of the expression 
 of gata-3 , a transcription factor pivotal for th2 differentiation , 
 were also involved for il-27-mediated th1 differentiation 
 [ 4042 ] . it is now clear that the molecular basis of 
 il-27/wsx-1-mediated th1 initiation is the induction of t - bet , 
 which is reminiscent of the finding that the ifn- 
 stimulation of cells induces t - bet in a stat-1-dependent fashion 
 [ 43 , 44 ] . interestingly , even in the absence of wsx-1 , t - bet was induced at later time points after t cell stimulation ( our unpublished observation ) , presumably due to the small amount of 
 ifn- produced or a stat1-independent mechanism yet to be 
 determined . this delayed induction of t - bet may explain the restoration of ifn- production and il-12 
 responsiveness of wsx-1 t cells at later time points . in sharp contrast to the finding that il-27 is important for th1 
 promotion , recent reports also demonstrated that il-27 plays a 
 regulatory role in immune responses . wsx-1 mice , when infected with t. cruzi or 
 toxoplasma gondii , showed remarkable sensitivity to the 
 infection [ 45 , 46 ] . this high sensitivity to infection was not due to impaired th1 differentiation or ifn- production . unexpectedly , over production of various proinflammatory cytokines including inf- , tnf- , and il-6 was observed in infected wsx-1 mice , followed by lethal liver 
 necrosis . rosas et al . also reported severe liver immunopathology 
 in tccr- ( another name for wsx-1 ) deficient mice infected with 
 leishmania donovani . sources of the cytokines were not limited to t cells , but other types of cells such as 
 nk / nkt cells and macrophages also produced various cytokines . in 
 addition , wsx-1 cd4 t cells were more activated than wild - type cells in terms of cell cycle progression 
 and expression of surface activation makers . similarly , wsx-1 nkt cells produced more of the proinflammatory cytokines , inducing lethal liver damages in con 
 a - induced liver damage experiment , which is an experimental model 
 of viral or autoimmune hepatitis . although the 
 development of nkt cells were normal in wsx-1 mice , these wsx-1 nkt cells produced more ifn- and il-4 than wild - type nkt cells in response to con a or -galactosyl ceramide stimulation in vitro . when infected with m. tuberculosis , wsx-1 
 mice also suffered from liver damages and cachexia due to over 
 production of inflammatory cytokines , such as tnf- 
 . interestingly , wsx-1 mice harbored significantly lower bacterial loads over wild - type mice due to higher amounts of tnf- and ifn-. these results remind us of the fact that immunity against pathogens is a double - edged sword ; it kills the pathogens in one way but may hurt 
 the host in another way . beside the observations described above , 
 il-27 actually suppressed cytokine production - activated cd4 
 t cells   in vitro . il-27 also suppressed cytokine 
 production such as tnf- and il-12 by macrophages 
 [ 49 , 50 ] . in these reports , il-27 stimulation induced stat3 activation and concurrently suppressed cytokine production by lps - stimulated macrophages . interestingly , il-27 stimulation 
 appeared less effective in macrophage suppression than il-4 or 
 il-10 . stimulation of macrophages with il-4 , il-10 , or il-27 
 resulted in differential gene induction , suggesting distinct 
 suppression mechanisms by respective cytokines . wirtz et al . also reported the suppressive effect of il-27 on monocytes 
 and granulocytes reactive oxygen intermediate ( roi ) production 
 . administration of recombinant il-27 to mice in the septic peritonitis model resulted in higher mortality than 
 untreated mice due to reduced bacterial clearance by the down 
 regulation of granulocyte / monocyte function . collectively , these 
 data revealed the novel role of il-27/wsx-1 as an attenuator of 
 proinflammatory cytokine production and cell activation of t cells 
 as well as macrophages , to suppress excess of inflammation and/or 
 to cease immune responses . in this regard , a distinct ( but not mutually exclusive ) hypothesis 
 on the impairment of th1 responses in the wsx-1 mice should be described . artis et al . reported an overproduction of il-4 in l. major - infected wsx-1 mice and suggested that the overproduction of th2 cytokines at early phases of infection reciprocally suppressed the following 
 ifn- production and th1 development . similarly , artis et al . also reported that upregulation of th2 responses is independent from th1 impairment in t. muris - infected 
 wsx-1 mice , claiming that primary role of il-27 is the suppression of immune responses ( including th2 responses ) 
 but may not be the induction of th1 differentiation ( see   and see review by hunter et al . ) . although reconciliation of the two seemingly conflicting ideas awaits further analyses of 
 the role of il-27 in various settings , a recent report by our 
 group sheds light on this issue . in this report , 
 yoshimura et al . demonstrated that il-27 acts on nave t cells 
 for ifn- production while the same cytokine suppresses 
 cytokine production by affecting fully activated cells . therefore , 
 the activation status of the cells may be the key determinant for 
 the effects of il-27 . the underlying mechanisms for this immune / inflammation suppression 
 by il-27 are not fully elucidated . it has been reported that il-27 
 inhibited il-2 production by cd4 t cells thereby regulating 
 an excess of cell activation [ 54 , 55 ] . in wsx-1 mice ( or cells ) , however , not only il-2 production but also the production of various types of cytokines were augmented . additionally , the source of cytokine production was not limited to cd4 t cells , but other types of cells were also affected by wsx-1 deficiency . il-10 production 
 was unexpectedly augmented similarly by wsx-1 deficiency 
 [ 45 , 46 ] and the so - called regulatory t cells ( treg ) did not appear to be affected by the receptor deficiency . a 
 mechanism that collectively regulates cytokine production and/or 
 cell activation should be taken into consideration . il-23 , another il-12 cytokine family member , has recently been 
 described to induce the differentiation of a new subset of th 
 cells , namely , th17 [ 7 , 8 , 57 ] . th17 cells differentiate from 
 the same precursor cells as th1 or th2 cells , during which il-6 
 and tgf- plus il-23 are required . th17 cells exclusively 
 produce il-17 , an inflammatogenic cytokine , but not ifn- or il-4 . il-17 plays a pivotal role in the induction 
 of some inflammatory diseases such as experimental autoimmune 
 encephalomyelitis [ 7 , 59 ] , inflammatory bowel diseases , and rheumatoid arthritis . it has also been 
 reported that il-17 is critically involved in some forms of 
 infection , either by induction of inflammatory cytokines such as 
 tnf- or by recruiting neutrophils [ 10 , 11 ] , although 
 not much is known about the role of il-17 on the defense against 
 parasite infection at this moment . a recent report by stumhofer et al . revealed an intriguing function of il-27 in view 
 of its immune suppression . in their report , stumhofer et al . revealed that wsx-1-deficient mice chronically infected with 
 t. gondii developed severe neuroinflammation with a 
 prominent il-17 response we also reported that il-27 
 receptor - deficient mice infected with t. cruzi produced 
 more il-17 in the sera than wild - type mice . although the precise role of il-17 in pathogenesis of encephalomyelitis and 
 infection - induced inflammation has yet to be elucidated , 
 therefore , il-17 produced in response to pathogens appears at 
 least partially responsible for tissue damages induced by 
 inflammation . in both reports and one by it is interesting that 
 il-23 , a member of il-12 cytokine family , induces the development 
 of th17 for the induction of inflammatory responses while il-27 , 
 another member of the family , inhibits the th17 differentiation to 
 suppress inflammation ( figure 3 ) . availability of il-12 
 family cytokines plus other cytokines , such as il-6 and tgf- in the surrounding milieu , may determine the direction 
 of immune responses toward either augmentation or regression . il-27 thus may be a potential target for treating inflammatory 
 diseases of infection and autoimmune origin mediated by il-17 . the 
 molecular basis for the inhibition of th17 differentiation is 
 still unclear . while stumhofer et al . and batten et al . showed that 
 the il-27-meidated th17 inhibition is dependent on stat1 by taking 
 advantage of stat1-deficient mice , we demonstrated the requirement 
 of stat3 for this inhibition by using stat3-deficient t cells . although further elucidation of the molecular mechanisms for the 
 il-27-mediated th17 inhibition is required , it would be reasonable 
 to assume that appropriate balance of stat1 and stat3 activation 
 downstream of the receptor determines the function of il-27 
 signaling , as implicated by a transgenic mice study   or by examination of surface wsx-1 expression on nave and 
 activated t cells . since its discovery , il-12 has been the only th1-promoting 
 cytokine for more than 10 years . it has been well recognized that 
 the balance between il-12-induced th1 responses versus 
 il-4-mediated th2 responses determines the immune responses 
 against pathogens . discoveries of two other il-12-related 
 cytokines along with the new th cell population have been 
 challenging and changing the paradigm . as discussed in this 
 review , the il-12 family members play differential roles in 
 induction and maintenance of th1 responses during the time course 
 of infection / immune responses . il-27 is critical in the commitment 
 of th precursor cells towards th1 differentiation and il-27 
 receptor deficiency resulted in impaired th1 responses with high 
 susceptibility to l. major infection . while having some 
 overlapping functions , the members of the family also have 
 distinct roles during immune responses . il-23 , one of the new 
 comers to the family , augments inflammation by induction of th17 
 cells , while il-27 , the other new comer , attenuates inflammation 
 by suppressing cytokine production . these findings remind us of 
 the intriguing fact that immune responses are elaborately 
 regulated along the time course of infection to fight the 
 dangerous pathogens and to simultaneously avoid hazardous damage 
 to oneself . in this view , the multifaceted role of il-27 is 
 particularly notable . although the induction of th1 
 differentiation and suppression of cytokine production are 
 seemingly conflicting , these distinct functions are quite 
 reasonable when different target cells ( nave versus 
 activated ) and/or different time points ( early versus late phase 
 of activation ) are taken into consideration . it would be premature 
 to discuss the possibility of using il-27 for treatment of disease 
 because of the complexity of its role . however , further 
 elucidation of the molecular mechanisms underlying the two 
 distinct functions of il-27 signaling as well as clarification of 
 the situations where the two roles are differentially used will 
 ensure that it will eventually be possible to use il-27 either to 
 reinforce defense against infectious agents or to treat 
 infection - induced immunopathology and inflammatory diseases .