the intestinal epithelium is the largest surface area of the human body in direct contact with the external environment and exposed to a multitude of foreign microorganisms , macromolecules , and xenobiotics . as such
, a fine regulation of gut mucosal immune functions is needed to develop a prompt and self - limiting inflammatory response against harmful pathogens but also to maintain normal gut homeostasis when no potential threat is sensed .
complex interactions between different cell types , effectors of both innate and adaptive immunity , regulate the inflammatory status within the intestinal mucosa .
pro- and anti - inflammatory cytokines represent key players in shaping this network and maintaining the communication among various cell types ; balance among these mediators appears to be critical for gut immune homeostasis .
in fact , a broad wealth of evidence demonstrates the importance of cytokine dysregulation in the onset of inflammatory conditions of the gastrointestinal tract .
in particular , ibd , namely , crohn 's disease ( cd ) and ulcerative colitis ( uc ) , is characterized by a significant dysregulation of cytokine production , with , in general , an overabundance of proinflammatory mediators . for example , it has been shown that in the inflamed mucosa of ibd patients and colitis models , there is a perturbation of the balance between the proinflammatory cytokine , il-1 , and its naturally occurring antagonist , the il-1 receptor antagonist ( il-1ra ) , and that restoring this balance by exogenous administration of il-1ra ameliorates intestinal inflammation [ 2 , 3 ] .
as in the case of il-1 , other members of the il-1 family , such as il-18 , have also been implicated in the initiation and perpetuation of chronic intestinal inflammation [ 46 ] .  
the il-1 family of cytokines is constantly expanding , and , very recently , new members have been identified and studied , such as il-1f11 , il-1f6/8/9 , il-1f7 , and il1f10 , respectively known as il-33 , il-36 , il-37 , and il-38 . to date , of these novel members , il-33 is the best characterized in terms of function and biological effects since its initial description in 2005 .
however , controversy still exists as to its precise role in intestinal disorders , particularly in the development of ibd .
thus , the aim of this review is to summarize what is already established regarding the role of il-33 in the gi tract , while providing insight into the potential role of this novel il-1 family member in the pathogenesis of chronic intestinal inflammation .
  in 2003 , a novel 30  kd protein , localized the nuclei of endothelial cells , was identified and shown to be highly expressed in high endothelial venules of tonsils , peyer 's patches , and lymph nodes .
the authors recognized , within the amino - terminal part of this molecule ( aa 1160 ) , a novel homeodomain - like helix - turn - helix ( hth ) dna - binding domain .
as such , this protein was hypothesized to possess nuclear factor function , critical for the induction of a lymphatic endothelium phenotype , and was therefore coined  nuclear factor - high endothelial venules 
two years later , nf - hev was identified as a novel member of the il-1 family , shown to be the ligand for the former orphaned receptor , st2 , and renamed il-1f11 or il-33 . in this first report ,
il-33 was described as a potent enhancer of th2 responses , inducing the production of il-5 and il-13 .
il-33 was reported to be widely expressed in different cell types and within most organs throughout the body .
in fact , il-33 has been detected in cells of both hematopoietic origin , particularly in restricted populations of professional antigen presenting cells such as macrophages and dendritic cells , and in several different cell types of nonhematopoietic origin such as fibroblasts , adipocytes , smooth muscle cells , endothelial cells , bronchial and intestinal epithelial cells .
initially , it was thought that il-33 was synthesized as a full - length 30  kd protein ( full - length il-33 , f - il-33 ) and processed by caspase-1 upon inflammasome activation , resulting in an alleged 18  kd bioactive peptide in a similar fashion to the other major il-1 family members , such as il-1 and il-18 .
however , further investigation by three independent research groups revealed that the inflammasome paradigm for il-33 did not occur in the in vivo setting and , instead , demonstrated that f - il-33 possessed full bioactivity , while proapoptotic caspase-3 and -7 processed f - il-33 into less bioactive forms of 2022  kd ( cleaved il-33 , c - il-33 ) [ 1012 ] .
more recently , f - il-33 has been shown to serve as a substrate for neutrophil elastase and cathepsin g , resulting in 1822  kd peptides with an increased bioactivity of tenfold , suggesting a possible extracellular mechanism to amplify the effects of il-33 during inflammatory conditions . to add further complexity to this scenario ,
an alternative splice variant of il-33 ( spil-33 ) has been described that is 5  kd smaller than f - il-33 and lacks the exons cleavable by caspases , but possesses similar bioactivity to f - il-33 .  
figure 1 summarizes the current knowledge regarding the different il-33 isoforms / splice variants and their bioactivity .  
as previously mentioned , il-33 exerts its biological effects through the binding of its receptor , st2 , also known as il-1 receptor - like 1 ( il1rl1 ) , belonging to the toll - il-1 receptor ( tir ) superfamily .
st2 exists in two different splice variants , leading to the synthesis of proteins with opposite biological functions : st2l , a transmembrane receptor that activates downstream signaling upon il-33 recognition , and sst2 , a soluble molecule that likely serves as a decoy receptor by binding il-33 and decreasing its availability to st2l , the il-33 signaling receptor . similar to other tir receptors , st2l requires pairing to a coreceptor in order to initiate the downstream cell signaling cascade . as such
, the il-33 receptor complex consists of st2l and the il-1 receptor accessory protein ( il1racp ) , a tir member also involved in il-18 signaling .
st2 and il1racp interact through their tir domain with myd88 , traf6 , and irak1/4 , eventually leading to the activation of transcription factors , such as nf-b and ap-1 , which promote the production of several proinflammatory mediators .
( sigirr ) or tir8 , can also dimerize with st2 and likely acts as a negative regulator of the il-33/st2 signaling pathway , ultimately reducing il-33 's biological effects . to date , a very limited amount of information is available regarding the biologic and pathophysiologic relevance of il-33 isoforms / splice variants , st2 splice variants , and alternative st2/sigirr signaling .
since its first description , il-33 has been reported to be localized in barrier epithelia within organs / tissues in direct contact with the external environment , including the skin , airway , and gut epithelia , suggesting a possible role of this cytokine in early immune responses against invasive pathogens . moreover ,
several studies consistently show that normal mice injected with recombinant il-33 develop a marked epithelial cell hyperplasia in the pulmonary and gi tracts , together with an eosinophilic and mononuclear infiltration into the lamina propria , specifically localized in these barrier organs / tissues [ 18 , 19 ] .
interestingly , the production of a thick mucus layer is one effective mechanism aimed to enhance epithelial barrier function and infers protection of these mucosal organs .
it is commonly thought that these specific effects on intestinal epithelial cells are mediated by the th2 cytokine il-13 [ 20 , 21 ] , which is abundantly overexpressed after il-33 stimulation / administration ; however , the possibility that il-33 per se promotes epithelial differentiation towards a secretory type it may not be ruled out .
in fact , il-33 is also a potent inducer of th2 cytokines that are pivotal in mounting potent immune responses against helminthes and fungi ; in fact , early papers exploring il-33 function have pointed out its fundamental role in eliminating intestinal parasites .
for example , trichuris muris , a nematode capable of infesting the gi tract , induces the production of high levels of il-33 from the infected ceca of experimental animals . in this experimental setting
even though a significant increase of nk cells was detected in mesenteric lymph nodes ( mlns ) from scid and wild - type animals treated with il-33 , parasite clearance appeared to be mediated through t- and b - cell activation , as scid mice failed to eliminate t. muris upon il-33 administration .
il-33 appeared to have similar protective functions , enhancing host responses against other parasitic and bacterial threats , such as toxoplasma gondii , pseudomonas aeruginosa , and leptospira   infections , in different organ systems .
more recently , a growing body of evidence has shown that il-33 's protective effects against parasites are also mediated by a newly identified innate immune cell population , uniquely coined  nuocytes ,  named after 
the 13th letter of the greek alphabet , making reference to their ability to produce high levels of il-13 .
in fact , these innate effector leukocytes display unique phenotypic characteristics and are not aligned with any other known mature leukocyte population .
they express icos , cd45 , st2 , and il-17br and respond to il-33 and/or il-25 stimulation with a significant increase in il-13 expression .
in addition , the transcription factor , ror , has been described to be necessary for their development .
nuocytes appear to be early initiators of th2 responses , and their activation is pivotal in eliciting worm clearance after nippostrongylus brasiliensis infection , but a th2 response is not required for nuocyte activity , as their development occurs in th2 cytokine deficient mice and in rag2 knockout mice [ 19 , 26 ] . at the same time , similar il-33/il-25-responsive innate effector cell populations have been described by others .
characterized a population , namely , natural helper cells ( nhc ) , identified by the presence of cell surface st2 , c - kit , sca-1 , and il-7r , that reside in mesenteric adipose tissue and are organized in fat - associated lymphoid clusters .
identified similar cells , but not expressing either sca-1 or c - kit , which were coined innate helper 2 ( ih2 ) cells and that are widely distributed in mouse mln , spleen , liver , and bone marrow .
together , these novel cell populations and others ( e.g. , multipotent progenitor type 2 ( mpp ) cells ) are termed innate lymphoid cells ( ilcs ) and share significant biologic similarities . as such
, it may be hypothesized that ilcs represent different maturation steps or different differentiation phenotypes from the same hematopoietic lineage .
nonetheless , nuocytes , nhc , and ih2 cells are induced by il-33 and are pivotal in mounting effective immune responses against helminthes characterized by the overproduction of il-5 and il-13 and the induction of histopathologic changes in the gut mucosa , including epithelial / goblet cell hyperplasia and eosinophilic infiltration .
whether or not these novel innate cell populations are the only responsible for the induction of these pathologic features is still debatable , as it has been clearly shown that il-33 induces the production of chemokines for eosinophils   and may also directly affect epithelial cell biology .
it seems reasonable that during parasitic infestation , in order to induce a prompt innate response , cells constituting intestinal barrier , such as epithelial cells and macrophages / dendritic cells , act as a major source of il-33/il-25 ; however , at present , no experimental data are available to confirm this hypothesis ; novel experimental tools may provide important insights to this topic ; in fact , mice genetically engineered to have the -galactosidase - neomycin resistance fusion gene inserted in il-33 intron 1 , the il-33-lacz gene trap reporter mice , were recently described and used to specifically measure and localize il-33 promoter activity within mouse body ; indeed , these animals may be a valuable tool to identify the cellular sources of il-33 during health and disease conditions , such as parasitic infestations .
as a growing body of evidence confirms the importance of il-33-induced ilcs in the protection against parasites , to date , the potential role of these novel cells in spontaneous inflammatory conditions has not been fully characterized in models of intestinal inflammation .
il-1 family members , coordinating early innate responses and later adaptive immune responses , have been shown to play an important role in the pathogenesis of chronic intestinal inflammation , characterizing ibd [ 31 , 32 ] .
as such , il-33 appeared to be a promising candidate to be studied in the setting of human ibd .
in fact , in 2010 , four independent groups described the dysregulation of il-33 expression in patients with uc and to a lesser extent , cd [ 3336 ] .
consistently , all groups showed increased protein levels of il-33 within the inflamed mucosa of ibd patients compared to healthy controls , particularly in uc [ 3336 ] .
immunohistochemistry experiments revealed intense il-33 staining in lamina propria inflammatory infiltrates , primarily localizing in cells that morphologically resemble macrophages and b cells / plasma cells .
importantly , nonhematopoietic cell types also contribute to the augmented production of il-33 during intestinal inflammation ; in particular , intestinal epithelial cells [ 33 , 35 , 36 ] and myofibroblasts   display the highest levels of il-33 during active ibd .
il-33 was also detected in other cell types within gut mucosa , confirming previous reports in other organ systems , with expression in fibroblasts , smooth muscle cells , endothelial cells [ 8 , 37 ] , and adipocytes .
il-33 was also detectable in the sera of ibd patients , with concentrations significantly increased compared to healthy controls [ 33 , 35 ] .
circulating il-33 levels were also found to be markedly reduced upon anti - tnf administration ( infliximab / remicade ) and may have the potential to be used as a marker of disease activity and/or response to anti - tnf treatment .
in fact , f - il-33 was the only form found to be present in both the cytoplasm and nuclei of il-33-producing cells , such as intestinal epithelial cells , whereas evaluation of mucosal biopsies revealed the presence of both f - il-33 and 2022  kd cleaved forms ; conversely , sera displayed exclusively the presence of the cleaved 2022  kd forms
. taken together , these data suggest the presence of extracellular proteases that have the ability to cleave il-33 , possibly modulating its bioactivity . as mentioned earlier ,
neutrophil elastase and cathepsin g are capable of cleaving f - il-33 , generating more potent forms .
as such , the inflammatory milieu characterizing ibd may have the potential to amplify il-33 's biological effects . on the other hand ,
similar to proapoptotic caspases , extracellular proteases may instead have the ability to inactivate f - il-33 , perhaps in an attempt to prevent possible harmful effects that may be triggered by high circulating levels of this cytokine .
indeed , further data are needed in order to clarify the significance of the circulating forms of il-33 and the mechanism(s ) leading to their generation .  
data regarding the analysis of il-33 expression in human ibd were closely recapitulated in samp1/yitfc ( samp ) mice , a spontaneous model of chronic intestinal inflammation immunologically characterized by an early th1 response and a later mixed th1/th2 phenotype , both significantly contributing to the extent of disease severity in these mice [ 40 , 41 ] . in this study ,
samp mice were shown to display high il-33 levels in the serum as well as the gut mucosa , consistently localized to intestinal epithelial cells and macrophages within the lamina propria .
interestingly , mucosal expression of il-33 was found to positively correlate with the severity of samp enteritis .   
a substantial alteration of st2 expression as well was detected in the intestinal mucosa and sera from ibd patients .
st2 was abundantly expressed in the inflamed mucosa of ibd patients compared to healthy controls , and similarly , elevated circulating levels of sst2 were shown in uc and cd patients [ 33 , 35 ] , correlating with mucosal st2 expression and both clinical and endoscopic disease activities .
indeed , this interesting piece of data may suggest that serum il-33/sst2 is produced within intestinal mucosa and directly reflects the severity of mucosal inflammation ; as such , it would be worthwhile to investigate the role of circulating il-33 and sst2 as markers of disease . besides quantitative differences of st2 expression , striking qualitative alterations were detected in the inflamed ibd mucosa versus healthy tissues .
st2 was constitutively expressed by intestinal epithelial cells during normal conditions ; however , in chronically inflamed ibd mucosa , intestinal epithelial cells lose st2 expression , which is redistributed to other inflammatory cell types . specifically , intestinal epithelial cells of uc patients did not present st2 , whereas st2 localized to lamina propria professional antigen presenting cells and t helper lymphocytes .
if a robust increase of st2-positive cells within the lamina propria infiltrate is a common feature of different inflammatory conditions of the gut , the epithelial reduction / disappearance of st2 appears to be specific for ibd .
in fact , in nonspecific colitides , such as infectious colitis and diverticulitis , st2 appears to be upregulated in both the epithelial and immune compartments of gut mucosa . of note ,
epithelial dysregulation of st2 refers to a marked decrease of st2l , the il-33 transmembrane receptor , but not of the sst2 protein [ 33 , 35 ] . as such
, this particular pattern of expression may suggest that during ibd , a severe impairment of il-33 signaling within the epithelial layer occurs , whereas il-33/st2 engagement may be enhanced in intestinal immune cells .
however , whether this alteration of epithelial st2l is a feedback response to the chronic exposure of elevated il-33 concentrations or an intrinsic epithelial defect characterizing ibd has yet to be determined . of note , during active ibd
, an intense st2 signal is detectable in perivisceral adipose tissue , where a rich infiltrate of st2-positive immune cells is evident .
consistent with recent data in the literature , this particular st2-expressing cell population , dispersed within mesenteric fat , may represent the nhc population , recently described by moro et al .
, that are pivotal for the onset of immune responses against parasites , but whose possible role in idiopathic intestinal inflammation has not yet been explored .
remarkably , as a further confirmation of the dysregulation of il-33 and st2 in human ibd , recent data , obtained in an italian cohort of adult and pediatric uc and cd patients , demonstrate that specific il-33 and st2 gene polymorphisms confer an increased risk of developing ibd ( both uc and cd ) , suggesting the involvement of the il-33/st2 axis in the onset of chronic intestinal inflammation .
despite robust data describing the changes in patterns of the expression of il-33 and st2 , current data regarding the role of this novel cytokine / receptor pair in the onset of ibd is conflicting and scarce .
in fact , while some studies suggest a proinflammatory function , others indicate a protective , anti - inflammatory role .
since its first description as a cytokine , il-33 has been shown to possess potent proinflammatory activity , inducing th2 cytokine production and promoting th2 immunity .
thus , il-33 was initially identified as a possible target for dampening inflammation in several animal models of inflammatory diseases , such as airway inflammation and arthritis ( i.e. , ovalbumin challenge - induced airways inflammation and collagen - induced arthritis ) [ 4446 ] since it was well established that il-33 had the ability to promote inflammation through both the recruitment   and activation   of immune cells to the site of inflammation , as demonstrated by data obtained in a th2 cell adoptive transfer model and in vitro .
consequently , mice overexpressing il-33 were reported to display spontaneous airway and lung inflammation , whereas blocking the il-33/st2 axis decreased inflammation in an experimental murine model of asthma . similarly , antagonizing il-33 's biological effects , using anti - st2 blocking antibodies ,
was effective in ameliorating joint inflammation in a murine model of rheumatoid arthritis ; in fact , the administration of il-33 to cultures of immune cells isolated from murine inflamed joints led to a dramatic increase in il-5 , il-6 , and il-17 production [ 45 , 46 ] .
unfractionated mln cells , collected from inflamed samp mice , secrete high levels of the aforementioned cytokines when cultured in the presence of il-33 . of note , both il-5 and il-6
have been shown to play a pathogenic role in samp ileitis , as demonstrated by the amelioration of intestinal disease following either anti - il-5 or anti - il-6 treatment [ 50 , 51 ] , whereas il-17 has been extensively characterized as a key cytokine in many immune - mediated diseases , including ibd [ 5254 ] .
along these same lines , unpublished data generated in our laboratory showed that blockade of the il-33/st2 axis significantly reduces intestinal inflammation in samp mice [ 5557 ] .
mechanistically , this effect appeared to be associated with a decrease of lamina propria eosinophil infiltration , by downregulating il-5 and eotaxin-1 and eotaxin-2 , and by reducing the percentages of il-17 producing macrophages , a population that has previously been described in intestinal and airway inflammatory conditions [ 58 , 59 ] .
however , a full phenotypic and functional characterization of this nonclassical cell population has not yet been performed .
in addition , il-33-induced inflammation may play a role in the development of intestinal fibrosis , as samp mice treated with anti - st2 blocking antibodies show decreased collagen deposition within the intestinal wall , together with a reduced production of pro - fibrotic molecules , such as transforming growth factor ( tgf)- , connective tissue growth factor ( ctgf ) , collagen-1 , insulin growth factor ( igf)-1 , and matrix metalloproteinase ( mmp)-9 .
consistently , healthy akr mice treated for one week with intraperitoneal injections of recombinant il-33 developed a marked thickening of muscularis layer of the intestinal wall , which was accompanied by increased expression of collagen-1 , collagen-3 , igf-1 , and ctgf .
these data , along with the observation that in vitro il-33 stimulation of human subepithelial myofibroblasts ( semf ) induces the expression of profibrogenic genes such as col1a1 , col3a1 , ctgf , and tgfb1 , suggest that il-33 may also play an important role in promoting inflammation - associated gut fibrosis , as reviewed by lopetuso et al . .  
additional data , primarily obtained from chemically induced models of intestinal inflammation , provide further insight into the role of il-33 and st2 in gut inflammatory conditions .
induced colitis in il-33 knockout ( ko ) mice and wild - type littermates using dextran sodium sulfate ( dss ) administration . the colonic inflammation caused by dss
is primarily initiated by disruption of the epithelial barrier , which results in bacterial translocation into the underlying lamina propria . in this model , the resulting inflammation
is mediated by the activation of innate immune responses and occurs in a t - cell - independent manner . during the acute phase of this experimental model , il-33 ko mice presented with reduced histologic inflammatory scores , with a significant reduction of granulocyte infiltration when compared to wild - type mice .
other independent groups replicated similar results , using the same acute animal model [ 6365 ] ; in addition , sedhom et al . confirmed the pathogenic role of il-33 also in a different model of intestinal inflammation , the trinitrobenzene - sulfonic - acid- ( tnbs- ) induced colitis , which is obtained throughout the chemical haptenization of protein expressed within the gut wall .
interestingly , sedhom et al . demonstrated on both dss- and tnbs - induced colitis that , during the onset of intestinal inflammation , the il-33/st2 axis activation was able to affect the non - haematopoietic component of the inflammatory response , resulting in a significant impairment of the epithelial barrier function .
conversely , results obtained by oboki et al . , during the recovery phase of the dss - induced colitis in il-33 ko mice , suggest that il-33 might have different roles during different phases of the inflammatory process ; in fact , weight recovery was markedly delayed in il-33 ko mice , with a slight increase in mortality rate .
these results suggest that il-33 is a critical amplifier of innate immune responses within the gut mucosa , whereas its role in the maintenance of chronic inflammation is less clear .
alternatively , il-33 may possess an important functional role in enhancing innate immune responses related to bacterial clearance or in promoting mucosal wound healing . despite its well - known proinflammatory properties , il-33 has also shown protective functions in different diseases ; in fact , early reports demonstrated that il-33 exerts a cardioprotective effect , reducing overload - induced cardiomyocyte hypertrophy ; on the same line , miller et al .
showed that il-33 reduced the development of atherosclerosis   and the inflammation within the adipose tissue of obese mice , confirming the beneficial effect of il-33 on the cardiovascular system .
in addition , il-33 appeared to have some protective role on various inflammatory conditions as well .
for example , il-33 appears to reduce inflammation in con - a hepatitis , in central nervous system demyelinating disorders , and in pancreatitis .
moreover , the ability of il-33 to recruit neutrophils to the site of inflammation has been shown to reduce the consequences of severe septic events , whereas the il-33-mediated expansion of il-4-producing basophils , upon high - dose immunoglobulin administration , has been shown to induce profound immunoregulatory effects .
the dichotomous nature of il-33 has also led to the generation of conflicting data in the setting of intestinal inflammation .
in fact , data generated on the spontaneous enteritis characterizing samp mice suggests a frank pathogenic role , while il-33 ko mice undergoing dss colitis develop a mixed response . in addition , chronic dss colitis appears to be less severe after il-33 administration . in these studies ,
gro et al . induced both acute and chronic dss colitis in balb / c mice and administered il-33 to experimental animals using different protocols .
when il-33 was injected during the first cycle of dss , colonic inflammation was more severe , with a dramatic increase in neutrophil infiltration ; conversely , treating animals during the recovery phases of both acute and chronic dss colitis decreased inflammatory scores and improved epithelial regeneration .
a different group reported partially overlapping results using a similar acute dss protocol . utilizing the acute dss colitis model , imaeda et al .
in these studies , the authors reported increased inflammatory scores in il-33-treated balb / c mice ; however , when evaluating the epithelial layer , complete reversion of the goblet cell depletion characteristic of dss colitis was observed .
this effect appeared to be mediated by the suppression of notch ligand expression by semfs .
in fact , the notch pathway is a key regulator of epithelial cell differentiation , leading towards an absorptive phenotype . as such , il-33-mediated inhibition of the notch pathway resulted in the maturation of epithelial cells towards a goblet cell phenotype , likely representing a protective response against harmful conditions .
interestingly and along similar lines , il-33 expression has been reported in semfs underlying ulcerated epithelia in uc and gastric ulcers [ 34 , 75 ] .
in addition , recent data suggest that il-33 stimulation may increase gastric epithelial proliferation , whereas dramatic changes in the pattern of il-33 expression in endothelial cells have been described during angiogenesis .
overall , these data together strongly suggest that the il-33/st2 axis may be implicated in the maintenance of intestinal barrier function , wherein perturbations may likely play an important role in the development of chronic inflammatory conditions of the gut .
as such , we can speculate that il-33 may enhance bacterial clearance by inducing early granulocyte infiltration , promoting epithelial differentiation towards a mucus - secreting phenotype , and by facilitating wound healing .
the redistribution / loss of st2l within the epithelial compartment described during uc [ 33 , 35 ] is consistent with the goblet cell depletion characterizing this particular disease and can also account for a defective wound healing process that can contribute to the chronicity of the inflammatory process .
data generated by duan et al . using the th1-driven tnbs - induced colitis , opposing to what was shown by sedhom et al .
, mice developed less severe colitis following intraperitoneal injections of il-33 , whereas anti - il-33 antibody administration did not significantly affect intestinal inflammation .
the anti - inflammatory effects of il-33 appeared to be mediated by a decreased production of the prototypic th1 cytokine , ifn , while the th2 cytokines , il-5 and il-13 , were found to be increased .
in addition , the authors also infer that il-33 has the ability to promote tolerogenic dendritic cell development , which ultimately results in the expansion of the t regulatory cell population .
thus , during th1-driven inflammation , il-33 may have the capability to modulate gut mucosal immune responses to a more th2-driven phenotype and promote the expansion of regulatory cell types .
the different functions of the il-33/st2 axis during intestinal inflammation in samp spontaneous enteritis and in the chemically induced dss- and tnbs - induced colitis models are recapitulated in figure 2 .
indeed , the il-33/st2 axis appears to be widely represented throughout the whole body , having different , and sometimes opposing , functions .
the resulting balance between the differential effects appears to be straightforward in certain tissue / organ systems , such as the airways / lungs or the joints , where inflammation , in itself , is the major detrimental agent to cause pathology . in more complex systems , wherein mucosal immune responses interact with a large bacterial load and epithelial barrier integrity and function is essential to consider , such as that found in chronic intestinal inflammation , the final outcome of this intricate interplay is difficult to predict and may vary according to slightly modifications of the initial conditions .
in fact , il-33 appears to enhance intestinal inflammation in disease models , which are driven by th2 and innate immune responses , such that observed in samp mice and the acute phase of dss colitis , and possibly in uc patients .
conversely , il-33 's effects during a th1-driven model , such as in tnbs colitis , may result in decreased intestinal inflammation mediated by cytokine and cell - mediated modulation of immune responses . on the other hand ,
emerging evidence suggests that il-33 may have positive effects on epithelial repair and barrier function .
high levels of il-33 during acute inflammation are likely to worsen tissue damage , whereas they may enhance tissue repair during recovery , promoting wound healing and the restoration of the epithelial barrier , as shown in the dss model .
thus , the initial features of the specific immune response and the timing of il-33 administration / blockade may dictate the overall outcome of disease pathogenesis .   the nuclear localization sequence in il-33 's primary structure suggested a possible role and function for this cytokine as an 
alarmin ,  that is , a protein released from dying / suffering cells as an extracellular sign of danger .
consistent with this hypothesis is the fact that il-33 is released by cells undergoing mechanical stress   and is cleaved by pro - apoptotic caspases into less active forms [ 1012 ] .
moreover , data obtained on mononuclear cells confirm that il-33 is overexpressed after tlr-2 and -4 stimulation , but it is released only when necrosis of these cells is induced . on the same line , it has been shown that other danger signals , such as extracellular atp , different pathogen - associated molecular patterns ( pamps ) , and inflammasome activation , lead to the increased production of il-33 in different cell types ( i.e. , glial cells , airway epithelial cells ) [ 8284 ] . indeed ,
the  alarmin  paradigm may have the potential to reconcile how il-33 possesses such a wide spectrum of effects in the gastrointestinal tract .
that is , upon harmful stimuli , il-33 is released by suffering epithelial barrier cells in order to recruit and activate immune cells and clear potential pathogens . at the same time , the presence of a defective and damaged epithelial barrier must be quickly repaired , and the need for prompt epithelial restitution and wound healing is promoted .  
interestingly , ibd genetic studies have identified a few candidate susceptibility genes , encoding proteins that are pivotal for the maintenance of epithelial cell integrity , such as the endoplasmic reticulum stress protein , proteins related to the autophagy process , and structural proteins .
it is tempting to speculate that when epithelial function is severely impaired as a consequence of mutations of the aforementioned genes , suffering intestinal epithelial cells may release high levels of il-33 , activating a potentially detrimental immune response . at the same time
, the loss / dysregulation of st2l on intestinal epithelial cells in ibd may alter epithelial restoration .
as such , further , more mechanistic investigation is warranted to dissect this complicated scenario , aiming to clarify the specific effects of the il-33/st2 axis , at different times as well as the contribution of different cellular sources , in order to elucidate the predominant role of this complex cytokine system in the pathogenesis of intestinal inflammation .
 interleukin ( il)-33 is a recently identified cytokine belonging to the il-1 family that is widely expressed throughout the body and has the ability to induce th2 immune responses . 
 in addition , il-33 plays a key role in promoting host defenses against parasites through the expansion of a novel population of innate lymphoid cells . in recent years 
 , a growing body of evidence has shown that the proinflammatory properties displayed by il-33 are detrimental in several experimental models of inflammation ; in others , however , il-33 appears to have protective functions . in 2010 
 , four different research groups consistently described the upregulation of il-33 in patients with inflammatory bowel disease ( ibd ) . 
 animal models of ibd were subsequently utilized in order to mechanistically determine the precise role of il-33 in chronic intestinal inflammation , without , however , reaching conclusive evidence demonstrating whether il-33 is pathogenic or protective . 
 indeed , data generated from these studies suggest that il-33 may possess dichotomous functions , enhancing inflammatory responses on one hand and promoting epithelial integrity on the other . 
 this review focuses on the available data regarding il-33/st2 in the physiological and inflammatory states of the gut in order to speculate on the possible roles of this novel il-1 family member in intestinal inflammation . 