h pylori and autoimmune gastritis are the most common etiologic lesions that create an environment conducive to gastric inflammation , and both conditions increase gastric cancer risk . the correa pathway describes the progression from inflammation to atrophic gastritis ( loss of parietal cells ) , metaplasia , dysplasia , and ultimately to adenocarcinoma.3 , 4 gastric atrophy is a key step , because studies of resected stomachs from patients with intestinal - type gastric cancer have shown gastric atrophy in every case . atrophy , metaplasia ( including spasmolytic polypeptide - expressing metaplasia [ spem ] , thought to be a precursor lesion to gastric cancer ) , dysplasia , and neoplastic transformation all occur in a setting of inflammation and a complex milieu of cytokines.6 , 7 , 8 a better understanding of how cytokines regulate the degree of inflammation and the extent of epithelial cell changes is needed to better understand gastric carcinogenesis . the immune system is essentially a network that uses cytokines to facilitate communication between cells . cytokines signal similarly to growth factors , in that they are secreted or membrane - bound proteins that bind to specific receptors on target cells . many cytokines were first characterized by immunologists as proteins made by leukocytes that also act on leukocytes ( hence many are called interleukins ) . however , cytokines can act on a broad range of cell types including gastrointestinal epithelium.9 , 10 , 11 when a cytokine binds its cognate receptor , an intracellular signal is transduced by second messengers that ultimately leads to the activation of transcription factors . many cytokines activate janus - activated kinases ( jaks ) , signaling molecules that phosphorylate and activate signal transducers and activators of transcription ( stats ) , which dimerize when activated and translocate to the nucleus and regulate transcription . not all cytokines activate jak - stat signaling , and different signal transduction pathways can be used that ultimately activate transcription factors such as activator protein 1 , mitogen - activated protein kinases ( mapks ) , and nuclear factor kappa b  ( nf-b).12 , 13 , 14 , 15 in addition to their ability to act on immune cells and regulate the type and degree of inflammation , cytokines also act on epithelial cells and other cell types to  regulate secretion,9 , 16 proliferation,16 , 17 and differentiation.18 , 19 , 20 because of their broad and pleiotropic effects on immune and epithelial cells , cytokines are an obvious candidate for analysis as gastric cancer risk factors . many questions remain concerning the levels and types of cytokines that regulate gastric cancer development and progression . the answers to these questions will likely advance our understanding of the link between chronic inflammation and gastric cancer . in 1994 , the world health organization officially announced that h pylori was a risk factor leading to gastric cancer . since then , studies have found correlations between increases in inflammatory cytokines in h pylori  infected individuals with increased gastric cancer risk . one study found increased risk in h pylori  infected individuals with a particular genotype in the inflammatory cytokine interleukin ( il ) 1 ( il1b ) that led to increased production . similarly , studies have associated increased levels of il8 , a cytokine that attracts neutrophils and activates inflammatory genes , and an increased risk of atrophic gastritis and diffuse gastric cancer.22 , 23 , 24 genotypes of tnf , il10 , il1b , and il1rn are also reported to confer greater risk of gastric cancer.25 , 26 , 27 overall the evidence indicates that the types and amounts of cytokines made in response to h pylori infection have a significant impact on the risk of developing gastric cancer . h pylori infects the lumen of the stomach , where immune cells do not normally traffic . as a result , in most cases the immune response is unable to clear h pylori from the stomach , and inflammation becomes chronic . it is likely that the greater the inflammatory response , the greater the tissue damage , including parietal cell atrophy , and greater atrophy leads to metaplasia and dysplasia and increases gastric cancer risk for example , risk may depend on the types of cytokines made by different subsets of differentiated cd4 + helper t cells responding to h pylori or self - antigens such as h+/k+ adenosine triphosphatase ( atpase ) in the case of autoimmune gastritis . the major t helper ( th ) cells and the signature cytokines secreted by each include th1 cells that secrete interferon ( ifn)- , th2 cells that secrete il4 , th17 cells that secrete il17a and il22 , and th22 cells that secrete il22 . th1 responses and th17 responses are the predominant responses during cases of h pylori infection and autoimmune gastritis . several reports correlate il17a production with more severe disease and poor prognosis , suggesting il17a promotes tumorigenesis.29 , 30 , 31 studies have reported the following:tumor - infiltrating cd4 + th17 cells produce il17 in the tumor microenvironment and promote tumor progression in human gastric cancer;there are increased th17 cells infiltrating tumors in patients with advanced gastric cancer;gastric cancer patients have higher levels of il17 in serum and in cancer tissues ; andgenetic data indicate that il17a and il17f polymorphisms increase gastric cancer risk . tumor - infiltrating cd4 + th17 cells produce il17 in the tumor microenvironment and promote tumor progression in human gastric cancer ; there are increased th17 cells infiltrating tumors in patients with advanced gastric cancer ; gastric cancer patients have higher levels of il17 in serum and in cancer tissues ; and genetic data indicate that il17a and il17f polymorphisms increase gastric cancer risk . il17a is not only expressed by cd4 + th17 cells but can be made by natural killer cells , cd8 + t cells , and other cell types . furthermore , the il17 family of cytokines includes 6 members ( il17a , il17b , il17c , il17d , il17e , and il17f ) . whether any of the additional members of the cytokine family influence immune and/or epithelial cells during the progression from gastritis to gastric cancer remains to be determined . in 2009 , a distinct subset of cd4 + th cells that secretes the cytokine il22 , called th22 cells , was identified . since then il22 produced by cancer - associated fibroblasts was reported to promote gastric cancer cell invasion through stat3 and extracellular signal - regulated kinase activation . il22 receptors are expressed in gastric cancer tumor cells , with expression significantly related to lymphatic invasion and poor prognosis . these new findings are important because mapk signaling has been implicated in invasion and metastasis of gastric cancer . in addition , cytokines in the il12 family ( il12 , il23 , il27 , il35 ) , particularly il23 , are also upregulated in gastric cancer cell lines and in tissue from h pylori  infected individuals . two of these cytokines signal through the gp130 receptor , which is also used by several members of the il6 family of cytokines ( il6 , il11 , oncostatin m , and others ) . il6 , il11 , and other cytokines that signal through the gp130 receptors activate stat3 , and stat3 is reported to be overactivated in gastric cancer and gastric cancer stem cells , indicating poor prognosis.41 , 42 several additional cytokines are reported to be expressed in the inflamed gastric mucosa , including il10 , il32 , and il33.43 , 44 , 45 additional information is needed to understand how the complex milieu of cytokines that are present in an individual with chronic gastritis influences the risk of gastric cancer ( table 1 ) . there is much to learn , such as which cytokine receptors are expressed by various immune and gastric epithelial cells , which signaling pathways are activated and/or suppressed , and how different combinations and levels of cytokines might promote gastric oncogenesis and/or metastasis . studies in mouse models have provided valuable insight into some of these questions . some of the models and cytokines studied are briefly reviewed below.table  1human studies and cytokines implicated in gastric cancer progressiondata sourcecytokines implicatedgenetic associationsil1 , il8 , tumor necrosis factor- , il10 , il17a , il17fbiological datail10 , il17a , il22 , il23 , il32 , il33 human studies and cytokines implicated in gastric cancer progression for example , in response to infection with leishmania , c57bl/6 mice preferentially expand th1 cd4 + cells that produce ifn- , whereas the response in balb / c mice is dominated by th2 cells that produce il4 . this differential cytokine production has significant consequences , with balb / c mice being much more susceptible to infection and death.46 , 47 this dichotomy is also seen in murine models of helicobacter infection . th2-skewed balb / c mice were shown to clear bacteria more efficiently and develop less gastric pathology than c57bl/6 mice with a predominantly th1 immune response . these early studies demonstrated that changes in the cytokine milieu significantly affect gastric pathology resulting from infection , and this has been supported by evidence from both humans and mouse models that concurrent infection with helminthes is capable of ameliorating the pathologic th1 response by promoting a competing th2 response.49 , 50 additional studies have demonstrated the importance of cytokines for disease progression . although mice lacking cd4 + t cells do not develop gastritis in response to helicobacter , ifn- treatment in the absence of infection was sufficient for the development of gastritis , and il4 treatment before infection was capable of preventing inflammation . these studies suggest that although cd4 + t cells are important initiators of the inflammatory response to infection , composition of the cytokine milieu is also relevant to disease progression , regardless of cellular origin . it is also worth noting that although many studies have addressed the th1/th2 dichotomy , discovery of additional cd4 + th subsets such as th9 , th17 , and th22 warrant further investigation . il17a , the defining cytokine for the th17 lineage , has been implicated in the inflammatory response to helicobacter colonization in humans . it is also associated with more severe pathology in infected mice ; one recent study observed that il17a - deficient mice develop less severe gastritis in response to infection . thus , it is unlikely that any one cytokine is responsible for all changes in epithelial cells that predispose to gastric pathology . it is most likely that cytokines can enhance and oppose each other s effects on the gastric epithelium , either promoting or preventing disease progression . the regulation of the immune response by ils and other cytokines is well - documented , and the difference in pathology caused by helicobacter is due in part to regulatory effects on the immune system . for instance , il4-deficient mice have more severe gastritis during infection that is correlated with higher levels of ifn- production , and ifn-deficient mice have less severe gastritis with greater proportions of il4 producing cells . t - cell transfer studies into immunodeficient mice demonstrated that il10 expression by regulatory cd4 + t cells is required for their ability to suppress t - cell  mediated gastritis caused by h  pylori infection . direct signaling by cytokines into gastric epithelial cells is also important to disease progression , which is evident by the fact that dysregulated gp130 signaling in the gastric epithelium is common in chronic infection and gastric cancer in humans . this signaling pathway has been further implicated in helicobacter - mediated gastritis by studies showing that il11 , which is one of many cytokines that signal through gp130 , is upregulated in infected mice , and treatment with il11 causes epithelial cell changes similar to chronic atrophic gastritis . in addition , a mouse model with defective transforming growth factor- receptor signaling localized to the gastric epithelium had higher incidence of gastric pre - neoplasia after infection , and downstream signaling molecules for transforming growth factor- receptor such as smad3 and smad4 have also been implicated as important repressors of gastric tumorigenesis.58 , 59 , 60 other signaling pathways are also involved ; it was recently shown that helicobacter induced the stem cell marker sox9 in metaplastic gastric epithelial cells in an il1 receptor  dependent manner . cytokines produced by the gastric epithelium are also capable of regulating the nature of the inflammatory response ; gastrokine-2 , a secreted protein normally produced by the gastric mucosa , was shown to restrain th1 responses but have no effect on th2 , th17 , or regulatory cd4 + t cells cytokines . overall , murine helicobacter models have increased our understanding of how cytokines made in response to infection can influence gastric cancer risk . these studies have revealed a complex series of relationships in which cytokines from a multitude of sources regulate the type and degree of the immune response , influence epithelial cell changes , and affect the degree of bacterial colonization . mouse models have been developed to study the influence of cytokines on gastritis and gastric epithelial cell changes that do not involve helicobacter . although none of these models develop adenocarcinoma , several interesting findings have shown that cytokines can act on immune cells to regulate the type and degree of inflammation and on gastric epithelial cells to regulate atrophy , hyperplasia , metaplasia , and tumor formation . the studies discussed below describe a number of different cytokines that likely contribute to inflammation , atrophy , and metaplasia in the stomach . ifn- is the signature cytokine made by th1 cells , but its exact role(s ) in regulating epithelial cell changes is unknown . one study showed that infusing ifn- into mice for 2 weeks caused mucous neck cell hyperplasia . the same group used a huntington interacting protein 1 related knockout ( hip1r/ ) mouse model of gastric metaplasia and showed that ifn- deficiency selectively reduced the extent of mucous neck cell hyperplasia but did not affect the expansion of surface mucous cells , loss of parietal cells , or loss of zymogenic cells . more recently petersen et  al showed that ifn- expression was not required for metaplasia ( spem ) to develop in an acute model of parietal cell collectively these 3 studies showed that ifn- expression was not necessary for atrophy or metaplasia ( spem ) in these models . however , when ifn- was expressed in mice under the control of a parietal cell specific promoter ( h / k atpase promoter ) , mice spontaneously developed inflammation , loss of parietal and chief cells , metaplasia ( spem ) , and dysplasia . to further complicate interpretation , another group generated ifn- expressing mice using the same h / k atpase promoter and found that ifn- played a role in suppressing inflammation and epithelial cell changes . these studies highlight the complexity of studying pleiotropic cytokines such as ifn- on gastric epithelial cell changes in various models . however , it is important to note that in the context of chronic atrophic gastritis , the cell types and relative levels of ifn- production may vary , and inflammation may also affect responsiveness of different epithelial cells to ifn- and other cytokines . the cytokine receptor gp130 is a ubiquitously expressed , signal transducing receptor that heterodimerizes with a number of different co - receptors that bind : il6 , il27 , il35 , leukemia inhibitor factor , oncostatin m , ciliary neutrophic factor , and cardiotrophin 1 . the importance of this cytokine receptor in gastric cancer was identified in mice that express a transgene with a mutation in the suppressor of cytokine signaling 3 binding site of gp130 that leads to constitutive activation . the cytokines il6 are believed to drive gastric tumorigenesis in these mice , in part through their ability to activate stat3 , a known driver of inflammation - associated tumorigenesis.70 , 71 findings in this model importantly identify gp130 as a cytokine receptor that directly regulates gastric epithelial cell changes associated with cancer . for example , il1 was shown to induce severe gastric dysplasia when expressed under the control of h / k atpase promoter , in part because of the recruitment of myeloid - derived suppressor cells . future challenges will be identifying which of the many cytokines present in chronic inflammation promote or inhibit tumors , and whether these activities are due to their ability to regulate immune or epithelial cell biology . recent studies have reported that patients with severe autoimmune gastritis ( pernicious anemia ) are up to 4 times more likely to develop gastric cancer than individuals who do not have disease.73 , 74 mouse models of autoimmune gastritis can provide insight into the link between gastritis and gastric cancer . mchugh et  al cloned a t - cell receptor from a mouse that had developed autoimmune gastritis . the t - cell receptor was specific for a peptide from h / k atpase , and expressing this t - cell receptor as a transgene in balb / c mice ( called txa23 ) caused autoimmune gastritis to develop spontaneously and with complete penetrance . it was recently shown that txa23 mice develop gastritis , oxyntic atrophy , metaplasia ( spem ) , and several other features associated with human gastric carcinogenesis . despite the fact that these mice are on a balb / c background , inflammation is predominantly mediated by ifn- producing cd4 + t cells ( th1 ) and il17 producing cd4 + t cells ( th17).76 , 77 these mice have been used to study the importance of cd4 + regulatory t cells in suppressing cytokines and reducing the severity of gastritis and oxyntic atrophy78 , 79 and to show that cd4 + t cells that produce ifn- ( th1 ) , il17 ( th17 ) , and il4 ( th2 ) are all capable of inducing gastritis and oxyntic atrophy , although with varying degrees and types of gastric pathology.80 , 81 other models of autoimmune gastritis have shown that neutralizing the cytokines il21 and tumor necrosis factor suppressed disease development . future studies in these mice will provide valuable insight into the cytokines that promote and suppress inflammation and epithelial cell biology in a setting of chronic inflammation . epithelial cells are also a source of cytokines that may regulate gastritis and gastric cancer . recently , il33 was reported to be highly expressed in gastric epithelium , particularly by surface mucous cells . il33 is a member of the il1 family of cytokines that binds to st2 ( il1rl1 ) and il1 receptor accessory protein il1rap and activates nf-b and mapk signaling . administering il33 in large doses to mice induced inflammation , atrophy , and metaplasia in the fundus , induced il6 and il9 expression , and promoted the expansion of myeloid - derived immune cells in the stomach . recently , il33 was shown to be important for spem development via an il13-dependent mechanism in a model in which parietal cells are depleted with l635 . il11 is expressed by epithelial cells in the fundic mucosa , especially by parietal cells . like il6 , il11 binds to gp130 in combination with another receptor subunit , il11 receptor alpha , to activate jak - stat signaling pathways . injecting mice with il11 was shown to induce atrophic gastritis . these recent findings have added il33 and il11 to list of cytokines ( table 2 ) that require additional investigation to increase understanding of the regulation of inflammation and epithelial cell changes in the stomach.table  2mouse studies and cytokines implicated in precancerous changesepithelial changeassociated cytokines / cytokine receptorsparietal cell atrophyil4 , il6 , il11 , il33 , ifn- , gp130 receptorneck cell hyperplasiail1 , il6 , ifn- , gp130 receptormetaplasiail1 , il6 , il11 , il13 , il33 , ifn- , gp130 receptor , transforming growth factor- mouse studies and cytokines implicated in precancerous changes studies in humans and mouse models of gastritis and gastric cancer are identifying important roles for cytokines in regulating oxyntic atrophy , hyperplasia , metaplasia , and progression to gastric cancer , but more information on cytokines that influence gastric cancer development is needed . furthermore , these cytokines functions ( pro- vs anti - tumorigenic ) and cellular targets ( immune vs epithelial ) will enhance understanding of how inflammation and cytokines influence gastric cancer risk . as new biologics are developed to target specific cytokines and cytokine pathways to treat a number of different inflammatory diseases , a better understanding of which cytokines promote gastric cancer development and progression may be used to develop additional therapeutic options for patients with chronic atrophic gastritis and gastric cancer .
chronic inflammation caused by infection with helicobacter pylori and autoimmune gastritis increases an individual s risk of developing gastric cancer . more than 90% of gastric cancers are adenocarcinomas , which originate from epithelial cells in the chronically inflamed gastric mucosa . 
 however , only a small subset of chronic gastritis patients develops gastric cancer , implying a role for genetic and environmental factors in cancer development . 
 a number of dna polymorphisms that increase gastric cancer risk have mapped to genes encoding cytokines . 
 many different cytokines secreted by immune cells and epithelial cells during chronic gastritis have been identified , but a better understanding of how cytokines regulate the severity of gastritis , epithelial cell changes , and neoplastic transformation is needed . 
 this review summarizes studies in both human and mouse models , describing a number of different findings that implicate various cytokines in regulating the development of gastric cancer .