tuberculosis(tb ) , caused by mycobacterium tuberculosis ( mtb ) , remains a leading cause of morbidity and mortality globally 1 . the chronicity of tuberculosis mirrors the complex interaction between the pathogen and the host 2 . the hiv coinfection and emergency of multidrug and extensive drug resistant mtb further exacerbated the predicament of tuberculosis control 3 . mycobacterium bovis bacillus calmette - guerin ( bcg ) , the only vaccine available for tb , was plagued by its limited and sometime unstable efficacy 4 . the interleukin ( il)-10 family of cytokines includes six immune mediators ( il-10 , il-19 , il-20 , il-22 , il-24 and il-26 ) with similar protein motif , receptor complex and conserved signaling cascades 6 , 7 . their biological effect is diverse and widely ranges from anti - inflammatory to pro - inflammatory 6 . two subfamilies exist based on the biological effect , immune regulatory cytokines including il-10 only , and il-20 subfamily consisting of the remaining five members ( il-19 , il-20 , il-22 , il-24 and il-26 ) 8 . the genes encoding il-10 , il-19 , il-20 and il-24 are located on the chromosome 1q32 6 . whereas , il-22 and il-26 encoding genes cluster with ifn - gamma gene on the chromosome 12q15 6 . / il-10rb 9 and results in the phosphorylation of stat3 , a critical transcription factor for the immunosuppressive effect of il-10 10 . il-19 , il-20 and il-24 induced their signaling through the il-20ra / il-20rb receptor complex . however , il-20 and il-24 interestingly , il-20 subfamily can also activate stat3 , but the outcome is different from the activation of il-10 11 . the role of il-10 family of cytokines in tuberculosis has been addressed recently 12 - 16 . here we discussed the roles of il-10 , il-22 , il-24 and il-26 in the context of tuberculosis . il-10 can be produced by hematopoietic and non - hematopoietic cells in response to mycobacterium tuberculosis complex infection ( figure 1 ) . bcg can activate the pattern recognition receptor ( prr ) on the surface of alveolar epithelial cells . the engagement of tlr2 and tlr4 on surface of epithelial cells by bcg can activate the glycogen synthase kinase-3 ( gsk3 ) by pi3k - akt and promote the production of il-10 and il-22 17 . however , conflicting evidence is that the suppression of gsk3 by chemical inhibitor can significantly boost the bcg induction of il-10 derived from macrophages 18 . in neutrophils , coactivation of tlr2-myd88- and c - type lectin receptor ( clr)- spleen tyrosine kinase ( syk)-dependent pathways led to the phosphorylation of p38 map and akt kinases and subsequently , the upregulation of il-10 19 . the interaction between the bcg - infected dendritic cells ( dcs ) with neutrophil through cd11b can activate myd88 and syk , to produce large quantities of il-10 20 . activation of erk by mtb rv1265 was critical for induced il-10 expression in macrophages 22 . binding of the mtb heat shock protein 60 to the tlr2 can activate macrophage p38 mapk to increase the il-10 production 23 . similarly , the engagement of mtb ppe32 with tlr2 can upregulate the il-10 production via co - activation of nf-b and mapk 24 . taken together , tlr2 and its downstream signaling mapk pathway are essential for the induction of il-10 expression in myeloid cells in response to the m. tuberculosis infection 25 . tlr3 regulates il-10 expression in response to mycobacterial - rna through the pi3k / akt signaling pathway 26 . bcg - stimulated il-10 expression in human macrophages by activation of dsrna - activated serine / threonine protein kinase ( pkr ) , which in turn activates mapk and nf- 27 . mtb promoted chemokine receptor 5 ( ccr5 ) expression in macrophages , which in turn increased il-10 production 28 . it was found that ifn- can induce il-10 production by macrophages through the phosphorylation of stat1 29 . this was supported by a murine study demonstrating that suppression of ifn-/ by tpl-2-erk1/2 signaling led to inhibition of il-10 production 31 . mtb infected antigen - presenting cells ( apcs ) can activate dap12 ( dnax - activating protein of 12kda ) required for irak - m ( interleukin-1 receptor - associated kinase m ) expression , which in turn induces il-10 production 32 . bcg can enhance the production of il-10 by binding to the dc - sign in dcs 33 . similarly , mannose - capped lipoarabinomannan ( man - lam ) can induce il-10 production through targeting the dectin-2 in apcs 34 . bcg induced high levels of il-10 production by cord blood dcs via upregulation of the nuclear transcription factor rel - b 35 . mtb can induce il-10 production by cd8 + t cells 36 , 37 { cyktor , 2013 # 1}{cyktor , 2013 # 1}. cd4 + t cells produced high levels of il-10 in response to purified protein derivative ( ppd ) 38 . il-22 is produced by cells of the lymphoid lineages in response to mycobacteria , which includes cd4 + cells ( th17 and th22 ) 39 , 40 and natural killer ( nk ) cells 41 ( figure 1 ) . stimulation of nk cells with mtb in the presence of il-15 led to dap10 expression and subsequently , il-10 production 42 . mtb psts1 upregulated il-22 secretion from memory cd4 + t was mediated via dcs 43 . il-24 is mainly produced by monocytes and activated t cells 46 , 47(figure 1 ) . il-26 is produced by myeloid and lymphoid lineages of white blood cells in response to mtb infection 13(figure 1 ) . il-26 can be released by th17 48 , 49 , th1 cells 48 and nk cells 50 . however , how mtb or its antigens regulate the expression of il22 , il-24 and il-26 remains to be elucidated . il-10 is a potent immunoregulatory cytokine indispensable for the host immunity against mycobacteria infection ( figure 2 ) . consistently , il-10 transgenic mice fail to control mtb infection and develop severe lung pathology compared with nontransgenic littermates 51 . however , il-10-knockout mice were more resistant to mtb infection and can limit bacterial growth within lung and spleen in comparison with the wild type 52 . blocking of murine il-10 signaling during mtb infection was beneficial for the control of the growth of bacteria and enhanced the survival of mice 53 . it was shown that il-10 -/- mice exhibited stronger th1 responses during mtb infection with concomitant massive pulmonary inflammation 54 . however il-10 transgenic mice show normal th1 response to mtb infection , but il-10 can reduce the production of antimicrobials reactive nitrogen intermediates ( no ) by macrophages via increased arginase-1 ( arg1 ) expression . furthermore , the expression of arg1 in hypoxic granuloma regions led to decreased t cells expansion 56 . the absence of il-10 enhanced the production of il-17 , and resulted in excessive lung inflammatory response 12 . similarly , blockade of il-10 during bcg vaccination can increase the protection against mtb challenge in both susceptible and comparatively resistant strains of mice due to enhanced th17 cell responses 57 . il-17a deficient mice failed to develop mature granuloma and protective responses against virulent mtb infection 58 . however , il-10-deficient mice infected with mtb can generate mature fibrotic pulmonary granulomas and improve the control of bacterial growth in the lungs 16 . furthermore , il-10 suppresses tnf- production 30 , 59 , 60 , tnf-is essential for granulomas formation and blocking of tnf-signaling leads to the disintegration of granuloma and dissemination of mtb 
 61 . moreover , il-10 can suppress the formation of multi - nucleated giant cells ( mgc ) from monocytes of tb patients in response to ppd 62 , the histologic hallmark of granuloma which can limit mtb infection . peripheral blood mononuclear cells ( pbmcs ) obtained from multi - drug resistant tb patients stimulated by esat6 displayed a lower frequency of ifn--producing t cells and a higher frequency of regulatory t cells ( treg ) correlated with increased il-10 secretion , when compared with cells from non - tuberculous mycobacteria patients . blockage of il-10 or il-10r with antibody can enhance th1 responses and decreases the treg cells 63 . dcs can uptake the apoptotic vesicle from the infected apoptotic macrophages and subsequently prime the nave t cells 64 . il-10 can suppress mtb - induced macrophages apoptosis by reducing tfn-and upregulating of bcl3 , an inhibitor of nf-b activity 60 . similarly , inhibition of macrophages apoptosis by virulent m. bovis was shown to be correlated with increased il-10 and bcl2 production and decreased tnf- production 65 . taken together , mycobacteria can subvert the apoptosis of macrophages for better survival and persistence . il-10 can interfere with antigen presentation by inducing march1 member of ubiquitin ligase family that interacts and degrades class ii major histocompatibility complex ( mhc - ii ) molecules 66 . it has been shown that il-10 pretreated monocyte - derived macrophages ( mdms ) failed to traffic the mtb peptide - mhc - ii complexes to the plasma membrane 67 . il-10 also inhibits mhc - ii expression in mtb - infected macrophages via activation of stat3 28 . suppression of il-12 and mhc - ii by il-10 in mtb - infected macrophages led to compromised the th1 responses 21 . consistently , blocking of il-10 signaling in mtb - infected macrophages can enhance il-12 secretion and augment the ifn- production by cd4 + t cells 68 . il-10 also can enhance mtb survival and growth in macrophages by suppressing phagosomal maturation partially dependent on stat3 activation 69 . taken together , il-10 enhances mycobacterial intracellular survival and growth by suppressing innate and adaptive immune response . the role of il-26 in host defense against mtb has been explored very recently ( figure 2 ) . the possible role of il-26 in mtb infection has been demonstrated by ex vivo study 13 . levels of il-26 are lower in the mtb - infected monocytes supernatants from tb patients than from healthy control 13 . the addition of recombinant il-26 to whole blood infected with mtb led to enhanced bacterial survival and growth 13 . however , how mtb downregulates il-26 and its role in antimycobacterial response remain to be explored . il-26 has quite unexpected cationic antimicrobials peptides properties that can lyse extracellular bacteria by forming membrane - pore 70 . also , it can bridge the released bacterial dna and tlr9 , thereby triggering the production of type i ifn by plasmacytoid dcs 70 . ifn-/ are potent inhibitors of the ifn- responsiveness and the production of type i cytokines that are required for protection against mtb infection 48 . il-26 produced by alveolar macrophages can recruit the neutrophils via induction of chemotaxis factors such il-8 and leukotaxin n - formyl - methionyl - leucyl - phenylalanine ( fmlp ) 71 . depletion of the neutrophil at the onset of tb infection results in significant increase the numbers of ifn--producing cd4 t - cells , correlated with reduced bacterial load and lung pathology 72 . in - depth understanding of il-26 biology it was predicted that the production of low levels of il-10 by activated macrophages is required to an efficient antimicrobial response , control of bacterial growth and to prevent lung damage 73 . therefore , modulation of il-10 levels during tb therapy might shorten the duration of the treatment and accelerate the bacterial clearance . it induces proliferative and anti - apoptotic pathways , as well as anti - microbial substances , that can enhance tissue repair and prevent its damage 11 . il-22 has been shown to be significantly upregulated in the blood from juvenile rhesus monkeys with severe tb disease 74 . il-22-producing t cells were found most frequent localized in lungs than in blood and lymphoid tissue , and involved in granuloma formation in macaque tb model 15 . interestingly , il-22 was found to be most significantly upregulated in pbmcs from vaccinated - protected cattle , when compared with vaccinated - unprotected and unvaccinated control , suggested that il-22 a potential biomarker for vaccine success 75 . however , il-22 may trigger the recruitment of b cells to the lungs by upregulating cxcl13 expression 77 . b cells play crucial roles in host defense by reducing inflammation and containment of mtb 
 78 . il-22-knockout mice challenged with mtb exhibited smaller b cell follicles in comparison with the counterpart 77 . administration of il-22 into the mice at the time of bcg vaccination led to reduced bacterial burden and enhanced cd4 + t cell responses after mtb challenge 41 . a polymorphism ( rs2227473 ) in the il-22 promoter was shown to be associated with tb susceptibility in chinese populations 79 . il-22 producing cd4 + t cells ( th22 ) frequencies were lowered in pbmcs from tb pleurisy ( ptb ) patients in comparison with healthy , whereas , il-22 was detected in high concentration in bronchoalveolar lavage ( bal ) fluid obtained from tb patients 80 . likewise , the th22 cells are elevated in tuberculous pleural fluid 40 , 81 , suggested that il-22 does involve in immunity at local site of mtb infection . in hiv patients with tb disease , il-22 was differentially induced in pbmcs collected from tb with reconstitution inflammatory syndrome ( tb - iris ) after in vitro stimulation with mtb , and higher concentration of il-22 proteins was detected in their serum , when compared with non - iris patients 82 . taken together , these data suggest that il-22 might play a decisive role in tuberculosis immunity . modern beijing strains can stimulate pbmcs from healthy individuals to produce lower level of il-22 than the ancient beijing and euro - american strains 83 . il-22 plays indispensable role in innate and adaptive immune defense against mtb infection ( figure 2 ) , production of il-22 by nk cells can inhibit intracellular growth of mtb through enhancing phagolysosomal fusion 42 . interesting , il-22 can be found in the membrane of mature cd4 + t effector cells and the direct interaction of these cells with mtb - infected macrophages led to suppress intracellular bacterial growth 84 . however , the molecular mechanisms by which il-22 inhibits intracellular growth of mtb are to be determined . recently , it was found that il-22 induced calgranulin a expression that can enhance phagolysosomal fusion by increasing rab7 expression and downregulatiing rab14 expression 85 . il-24 , also known as melanoma differentiation associated gene 7 product(mda-7 ) , has potent antitumor activity through selectively induced tumor death without detriment effect in normal cells 86 . levels of il-24 are significantly lower in the serum of tb patients in comparison with healthy volunteers 14 . il-24 expression was decreased in pbmcs infected with mtb , and addition of recombinant il-24 can induce ifn-production by cd8 + t cells 14 . il-24 was significantly upregulated in pbmcs obtained from bcg - japan strain - vaccinated children stimulated with culture filtrate proteins ( cfp ) of mtb compared with children vaccinated with bcg - brazil or bcg - denmark strain 87 . pbmcs obtained from latent tb patients ( ltb ) produces more il-24 than from active tb patients 88 . furthermore , exogenous il-24 can increase ifn-in pbmcs obtained from tb patients , however , neutralization of il-24 can reduce ifn-expression in pbmcs collected from ltb patients 46 . il-24 increased ifn-expression through increasing expressions of il-12 , 1l-23 and il-27 , and by decreasing foxp3 expression 46 ( figure 2 ) . taken together , mtb suppresses il-24 expression might enhance its persistence host tissue . however , in conclusion , il-10 family of cytokines has diverse roles during mycobacteria infection ranging from immune evasion to immune protective . il-10 can enhance the intracellular survival of bacilli via several means , namely 1 ) inhibiting phagosomal maturation , 2 ) reducing nitric oxide production and 3 ) blocking ifn-signaling in macrophage . in addition , il-10 can antagonize the development of th1 responses through suppressing antigen presentation and il-12 production . moreover , it can inhibit macrophages apoptosis that is require for efficient development of t cells responses . however , low level il-10 can trigger antimicrobial response and prevent tissue damage . therefore , decreasing the il-10 level during tb therapy might benefit for the rapid clearance of bacteria . il-26 is a novel player with scarce information in tb immune responses ; it can limit mtb clearance during in vitro infection of pbmcs by mechanisms currently unknown . understanding how il-26 enhances intracellular growth of bacilli is critical to develop better countermeasures against this notorious pathogen . il-22 plays a decisive role in innate and adaptive immune responses against mtb infection by promoting phagolysosomal fusion , expansion and ifn-production by memory cd4 + cells and recruitment of b cells . il-22 and il-24 , crucial for the coordinated cell - mediated immunity , might represent good candidates for better tb therapy .
the interleukin-10 ( il-10 ) family of cytokines consists of six immune mediators , namely il-10 , il-19 , il-20 , il-22 , il-24 and il-26 . 
 il-10 , il-22 , il-24 and il-26 are critical for the regulation of host defense against mycobacterium tuberculosis infections . specifically , il-10 and il-26 can suppress the antimycobacterial immunity and promote the survival of pathogen , while il-22 and il-24 can generate protective responses and inhibit the intracellular growth of pathogen . 
 knowledge about the new players in tuberculosis immunology , namely il-10 family , can inform novel immunity - based countermeasures and host directed therapies against tuberculosis .