tuberculosis remains a leading cause of death worldwide which afflicts approximately one - third of the world 's population and claims a death toll around 1.2 million annually 1 . mycobacterium tuberculosis ( mtb ) is an unusual facultative intracellular pathogen which multiplies within macrophage 2 . macrophages are crucial for the innate and adaptive immune response to mtb because of their potent antimicrobicidal activities , antigens - presenting abilities , secretion of inflammatory mediators such as the il-12 family of cytokines 3 , 4 , and their role in granuloma formation to control the pathogen 5 - 7 . however , mtb can persist within granuloma lifelong without clinical symptoms 3 , 4 , 8 . in - depth understanding of the underlying molecular mechanisms can inspire better drug design and treatment of tb . the interleukin-12 ( il-12 ) family , including il-12 , il-23 , il-27 and il-35 , are important for tb pathogenesis and control , which can regulate the th1 response 9 , 10 . interleukin-27 ( il27 ) was first discovered in 2002 as a new member of the il-12 cytokine family 11 . it is a heterodimer , comprised of p28 and ebi3 subunits that are structurally similar to the p35 and p40 subunits of il-12 12 . il-27 is largely secreted from activated antigen - presenting cells ( apcs ) such as macrophages and dendritic cells ( dcs ) 13 - 15 ( figure 1 ) . both subunits are essential 16 - 18 for activating janus kinase ( jak ) and transcription factor ( stat ) . specifically , stat1and stat 3 are predominant mediators of il-27 effects ( figure 2 ) 19 , 20 . il-27 has potent antitumor activities by activation of cytotoxic t lymphocytes cd8 + t cells 21 - 25 , natural killer ( nk ) cells 26 - 28 , nk t cells 28 and anti - angiogenic factors 29 , 30 . however , il-27r signaling was demonstrated to be involved in the potent antagonizing of th1 , th2 and th17 inflammatory responses 31 - 33 and agonist of tr1 cell response 34 , 35 . il-27 can ameliorate symptoms of autoimmune diseases in preclinical studies 33 , 36 , 37 . the expression level of il-27 in granuloma suggested a role in tuberculosis 38 . the elevated level of il-27 in tuberculous pleural fluid suggested a potential biomarker for tuberculous pleurisy diagnosis 39 , 40 . il27 is a heterodimeric cytokine consisting of p28 and epstein - barr virus induced gene 3 ( ebi3 ) subunits 16 , 44 . ebi3 expression is high in human b lymphoblast cell lines transformed in vitro by ebv , activated apcs and placental syncytiotrophoblasts 16 , 45 . the ebi3 reversibly binds to il-12p35-related subunit , namely p28 , to form heterodimeric cytokine il-2746 , 47 . the connection between p28 and ebi3 is labile and these subunits can be secreted independently 16 . the p28 is structurally similar to an il-6/il-12 family , composed of a long chain of four  helix bundle named a - d from the n terminus to the c terminus49 . the polypeptide loop connecting the p28 c and d  helices contains a stretch of polyglutamic acids ( poly - e ) unique among helical cytokines and is highly conserved 50 . the p28 alone can suppress il-27 mediated th1 responses 51 and il-6 mediated signaling 52 . these data suggest a regulatory role of p28 in il-27-mediated immune response . a polymorphism ( -964a > g ) in the p28 promoter has been noted in certain diseases such as asthma 53 , inflammatory bowel diseases 54 , chronic obstructive pulmonary disease55 , and epithelial ovarian cancer 56 , which seems to be associated with an increase in disease susceptibility . il-27 is mainly produced by activating apcs such as dcs and macrophages ( figure 1 ) . macrophages - stimulated with tlrs agonists , ( polyinosinic : polycytidylic acid ( poly ( i : c ) ) , lipopolysaccharide ( lps ) , or r848 can induce both subunits of il-27 13 . it has been reported that p28 production is completely dependent on the tlr4-associated myeloid differentiation factor 88 ( myd88 ) mediated pathway and partially dependent on nf-bc - rel transcription factor 14 . myd88 also regulates p28 expression through binding of ap-1/c - fos to the p28 promoter in both human and mouse macrophages . however , the binding of c - fos to the p28 promoter can be blocked by overexpression of p38 mapk 57 . in addition , tlr4 can induce the expression of p28 subunit through activating the tir domain - containing adaptor inducing ifn- ( trif ) and ifn regulatory factor 3 ( irf3 ) pathways 58 . tlr2 , tlr4 , and tlr9-associated myd88 are required for the induction of ebi3 expression through binding of nf - kb subunits ( p50/p65 ) and pu.1 to the ebi3 promoter 59 . ifn - alpha can promote the production of il-27 by enhancing the expression and binding of irf-1 to the ifn - stimulated response element ( isre ) in the p28 gene promoter 13 . likewise , ifn- induced irf-8 expressions can upregulate p28 gene transcription in synergy with irf-1 15 . ifn- can selectively induce il-27 expression via activating the c - jun n - terminal kinases ( jnk ) , mapks and the phosphoinositide-3-kinase ( pi3k ) signaling in primary human monocyte60 . il-27r consists of the class i cytokine receptor family ( tccr ) ( also known as wsx-1 ) and gp130 16 - 18 . il-27r is expressed in various cell types including nave t cells , nk cells , activated b cells , monocytes , dendritic cells , activated endothelial cells , and mast cells 61 . il-27 induced intracellular signaling involves phosphorylation of different isoforms of jak and stat , which varies with immune cell types : jak1 , jak2 , tyrosine kinase 2 ( tyk2 ) , stat1 , 2 , 3 , 4 and stat5 in nave cd4 t cells 62 , jak-1 , stat1 , stat-3 and stat5 in nk cells61 , 63 , stat1 , stat3 , and nf-b activation in monocytes 20 , and stat-3 in mast cells 64 . interestingly , the effect of the il-27 can be both pro - inflammatory and anti - inflammatory via same stat1/stat3 signaling . the pro - inflammatory role of il-27 as key inflammatory mediator for th1 differentiation and ifn- production has been intensively explored 16 , 63 , 65 . stimulation of th0 in the presence of il-27 induces the expression of the key signature th1 cytokine ifn- via up - regulating of the transcription factor t - bet and il-12r2 chain which is essential for responding to il-12 and the differentiation of a th1 phenotype 61 , 62 , 65 . this effect of il-27 on th cell depends on multiple transcription factors such as stat-1 and stat-3 61 , 62 , 65 . in vivo studies demonstrated the role of il-27 in th1 responses . in this context , it was shown that wsx-1-/- mice were more susceptible to leishmania major infection and impaired ifn- production 17 . similarly , reduced th1 responses and igg2a production was demonstrated in wsx-1-deficient mice infected with listeria monocytogenes 18 . moreover , it was shown that il-27r signaling is vital in vivo for the ifn- production by cd8 + t cells 66 . il-27 can enhance the proliferation of nave cd8 + t cells and ifn- and granzyme b production dependent on stat1 and stat3 22 . il-27 can stimulate human monocyte to express tlr4 through activation of stat-3 , and nf-b which subsequently respond to lps - inducing il-6 , tnf- , mip-1 , and mip-1 expression 67 . il-27 increased the production of nitric oxide from peritoneal macrophages via activation of stat-1 , nf-b and mapks 68 . il-27 also enhanced monocyte derived dendritic cells ( modcs ) to express il-27 , il-8 , cxcl10 , chemokine receptor ( ccr1 ) , ifn - stimulated genes , irf8 and other genes involved in antigen presentation 69 . il-27 negatively regulated tr1 cells by induction of metallothioneins ( mts ) which in turn reduced stat1 and stat3 phosphorylation resulting in impaired il-10 production 70 . il-27 can negatively modulate inflammatory processes . improved control of leishmania donovani correlates with massive inflammatory responses similarly , wsx-1-/- mice infected with toxoplasma gondii or trypanosoma cruzi generated robust ifn- responses and developed lethal t cell - mediated inflammation 31 , 72 . greater effector and memory cd4 + t cells responses were noted in il27r lacking mice challenged by plasmodium berghei 
 73 . the negative feedback of il-27 largely depends on the induction of type 1 regulatory t cells ( tr1 ) . il-27 can induce tr1 cells via various mechanisms including activation of stat1 , stat3 75 - 76 , upregulation of blimp1 77 , aryl hydrocarbon receptor ( ahr ) , transcription factor c - maf , inducible t cell costimulator ( icos ) , and il-21 production , which is indispensable for the expansion and maintenance of tr1 cells 34 , 35 . furthermore , the anti - inflammatory effect of il-27 needs more than the induction of tr1 cells . il-27r-/- cd4 + t cells produce more il-2 than wild - type during in vitro differentiation . the addition of recombinant il-27 suppressed the expression of il-2 both transcriptionally and translationally 78 . il-27 suppresses cd28-mediated il-2 production by stat 1 which in turn induces the expression of the suppressor of cytokine signaling 3 ( socs3 ) 79 . moreover , it was observed that wsx-1-deficient macrophages are more efficient in inducing ifn- and il-17a production by cd4 + t cells than control . il-27 can activate stat1 which in turn suppresses cyclooxygenase ( cox ) expression and followed by reducing prostaglandin ( pg2 ) secretion , which can affect the cd4 + t cell responses 80 . il-27 was also reported to suppress th2 cells development and their cytokines production by downregulation of gata3 and upregulation of t - beta in differentiated th2 cells 32 . in addition to suppress both th1 and th2 cells , il-27 can inhibit the development of th17 cells . consistently , it was demonstrated that il-27 can inhibit th17 cell development through various mechanisms including the suppression of il-6 signaling mediated il-17 production 33 , retinoid - related orphan receptor  ( ror ) expression ( th17-specific transcription factor ) 36 , and also via induction of the il-10 production 81 , and programmed death ligand 1 ( pd - l1 ) on nave t cells 37 . il-27 upregulates the expression of blimp1 in pre - committed th17 cells and acquired a tr-1-like phenotype characterized by the production of il-10 and ifn- 77 . more recently , it was recognized that il-27 can inhibit the development of th9 cells and limit its related encephalitis by mechanism partly depending on stat-1 82 . taken together , il-27 induces an immunosuppressive effect by both tr1 cells dependent and independent mechanisms . however , the contribution of il-27 in the induction of il-35-producing t regulatory cells remains unknown . the innate immunity plays a decisive role in the early clearance of mtb via the recognition of the antigen and subsequent induction of pro - inflammatory cytokines and antimicrobial peptides 83 . the production of il-27 in response to mtb infection modulates macrophage responses 41 - 43 . the combination of il-12 and anti - il-27r can limit mtb growth via upregulation of pro - inflammatory cytokines such as tnf- , ifn- , and il-1841 , 84 . however , the molecular mechanisms by which il-27 negatively regulated macrophages during mtb infections remain unclear . it was demonstrated that il-27r singling in mice peritoneal macrophages suppresses il-12 and tnf- production by stat3 43 . il-27 can antagonize il-18 signaling in human macrophages challenged with mtb by inhibiting the expression of the il-18 receptor beta - chain and il-18r downstream signaling component nf - kb 42 . il-18 and il-12 , synergistically induced ifn- production by human macrophages and promoted the killing of mtb 
 84 . it has been shown that il-27 can inhibit the expression of the phagosomal vacuolar atpase ( v - atpase ) and lysosomal integrated membrane protein-1 ( cd63 ) , resulted in the suppression of phagosomal acidification and cathepsin d maturation 85 . il-27 signaling is necessary for the il-10 production by macrophages through enhancing the activity and binding of stat1/stat3 to the il-10 promoter 86 . recently , it was found that il-10 induced by mtb during macrophage infection can manipulate phagosomal maturation to enhance its own intracellular growth 87 . most recently a study demonstrated that il-27 suppresses ifn- mediated autophagy in human macrophages infected with mtb by inducing autophagy negative regulatory factors mtor and mcl-1 through jak / pi3-k / akt and pi3-k pathway , respectively 88 . in brief , mtb can subvert the normal bactericidal function of macrophages by inducing il-27 ( figure 2a , table 1 ) . ablation of il-27 , either by disruption of the il-27r gene in mice or by an antibody blockade of the il-27r , implicates an important role of il-27 in adaptive immunity against mycobacteria infections . wsx-1-deficient mice have impaired ifn- production and granuloma formation when challenged with m. bovis bcg 89 . however , there are no differences in liver pathology and bacterial load between mutant and wild type mice 89 . significant elevation of il-27 throughout the infanthood and neutralization of il-27 in neonatal macrophages improved control of bacterial replication 90 . furthermore , blockade of il-27 during incubation with the m. bovis ( bcg ) augmented the ifn- production by allogeneic cd4 + t cells 90 . similarly , it has been demonstrated that improved control of mtb growth in the lungs results from increased production of pro - inflammatory cytokines in wsx-1-knockout mice 43 . these results suggest that il-27 negatively regulated th1 response ( figure 2b , table 1 ) , however , the underlying mechanisms remain elusive . more recently , it was recognized that il-27 positively regulates il-10 producing tr1 cells during chronic inflammation 34 , 35 , 75 - 77 ( figure 2b , table 1 ) . it has been demonstrated that il-10 suppressed the immune response to mtb infections without immunopathology observed in both c57bl/6 and cba / j mice 91 , 92 . moreover , it was shown that il-10-deficient mice were more resistant to m. bovis ( bcg ) challenge in comparison to control mice 93 . blocking of il-10r in cba / j mice improved m. bovis ( bcg ) evoked protection against mtb characterized by enhanced th1 and th17 responses and increased ifn- and il-17a production in the mice lungs 94 . taken together , these data indicate il-27 can modulate immune response against mycobacteria by inducing il-10 . il-27 directly mediated the suppression of the development of th17 cells in chronic inflammation models 33 , 36 , 37 , 81 ( figure 2 ) . th7 cells induce t cell chemokines ( cxcl9 , cxcl10 and cxcl11 ) in the lungs of infected mice to recruit ifn--producing cd4 + t cells to limit mtb growth 95 . bcg - induced th17 cells which can downregulate il-10 and generate th1 immune response resulted in protection upon mtb challenge 96 . il-17-deficient mice were more susceptible to mycobacteria , evidenced by the impaired granulomas formation and decreased ifn- production 97 . vaccination will elicit th17 cells response associated with increased pro - inflammatory cytokines , granulocytes infiltration and severe lung damage in mice 98 . the higher amount of th17 cells and related cytokines in active tuberculosis patients implicated a role in immunopathogenesis 99 , 100 . as an exceptional successful silent killer knowledge about the emerging player , namely il-27 , will inform better countermeasures against this hideous threat of global health public .
il-27 , a heterodimeric cytokine of il-12 family , regulates both innate and adaptive immunity largely via jak - stat signaling . 
 il-27 can induce ifn- and inflammatory mediators from t lymphocytes and innate immune cells . 
 il-27 has unique anti - inflammatory properties via both tr1 cells dependent and independent mechanisms . here 
 the role and biology of il-27 in innate and adaptive immunity are summarized , with special interest with immunity against mycobacterium tuberculosis .