inflammation probably evolved to defend against infection or irritants and also co - evolved to adapt to tissue injury and stress ( 1 ) . this view is largely based on the observation that the initiation of inflammation can be triggered by common sensors to recognize both exogenous inflammatory inducers called pathogen - associated molecular patterns ( pamps ) and endogenous danger - associated molecular patterns ( damps ) . inflammation is a tremendous price to pay for resolution of disruption to homeostasis ( 2 ) . results obtained from cd137-deficient mice indicated that cd137/cd137l interactions might be involved in inflammation in models of autoimmune disease , infection , allergy or septic shock . initially , it was thought that decreased inflammation in cd137-deficient mice was due to defects in the functions of lymphoid cells such as t cells , nk , and nkt cells or of myeloid cells such as neutrophils . recent studies , however , suggest that cd137 can regulate inflammation by influencing various immune cells in a negative manner . furthermore , it has been shown that reverse signaling through cd137l is essential in amplifying inflammation . in this mini - review , i discuss hypotheses that provide appropriate explanations for inflammation mediated by cd137 or cd137l signaling . observations showing that lower extents of inflammatory diseases occur in cd137-deficient mice or mice treated with cd137 blockers are considered to be evidence for the involvement of cd137 signaling in inflammation mediated by cd4 t cells . for example , there is a milder disease severity in the absence of cd137 signaling in various types of immunological diseases such as rheumatoid arthritis , atherosclerosis , acute coronary syndrome , autoimmune myocarditis , herpetic stromal keratitis , allograft rejection , and graft - versus - host disease ( 3 - 13 ) . cd137 signaling stimulates cd4 t cells to produce the proinflammatory cytokines , ifn- and tnf- ( 14 ) . nk and nkt cells also use a similar signaling pathway through cd137 in mediating sepsis and airway inflammation , respectively ( 15,16 ) . since cd137 is expressed in myeloid lineage cells , it was predicted that cd137 signaling would control inflammation by directly regulating their cellular activities . these cells include neutrophils ( 17,18 ) , mast cells ( 19 ) , eosinophils ( 20 ) , and dendritic cells ( 21,22 ) . for example , cd137-deficient neutrophils are defective in their activities for phagocytosis and radical oxygen species ( ros ) production , which is correlated with the susceptibility of cd137-deficient mice to listeria monocytogenes infections ( 17 ) . cd137 also may be involved in the resolution phase of inflammation , since its signaling can abrogate gm - csf - mediated anti - apoptosis in neutrophils ( 18 ) . cd137 signaling has positive and negative roles in mast cells and eosinophils for allergic inflammation , respectively : 1 ) cd137-deficient mast cells have defects in cytokine production and degranulation triggered by ige , suggesting that cd137 signaling mediates allergic responses through activation of mast cells ( 19 ) ; 2 ) activation of cd137 inhibits gm - csf- or il-5-mediated anti - apoptosis of eosinophils in atopic dermatitis patients and extrinsic asthmatics ( 20 ) . in contrast , cd137 is not expressed on eosinophils of patients with intrinsic asthma and idiopathic eosinophilia , therefore implicating that the absence of cd137 signaling is associated with the accumulation of eosinophils ( 20 ) . for example , cd137 is expressed in vessels of inflammation sites including endothelial cells and smooth muscle cells ( 4,5,23 ) . cd137 signaling in endothelial cells results in the production of cytokines and chemokines and upregulation of cell adhesion molecules . however , cd137 may be involved in breaking down inflammation by inhibiting vessel permeability ( unpublished data ) and smooth muscle cell proliferation ( 4 ) . it is interesting that regulation of acute versus chronic inflammation is governed by genetic background ( 12,24 ; unpublished data ) . for example , cd137-deficient c57bl/6 mice have more severe acute inflammation ( e.g. , acute graft - versus - host disease ) , while having less severe chronic inflammation ( e.g. , obesity ) . there is evidence showing that cd137 signaling regulates inflammation in a negative manner ( 25,26 ) . mesenteric lymph node dendritic cells express cd137 and cd137 signaling in these cells controls the development of inducible regulatory t cells in the galt by regulating retinal dehydrogenase , an enzyme that promotes the production of retinoic acid ( 25 ) . administration of anti - cd137 mab induces the expansion of regulatory t cells and its immunosuppressive activity ( 26 ) . our unpublished data indicate that cd137 signaling controls the regulatory activity of hepatic nk cells and subsequently influences liver ischemia - reperfusion injury . in sum cd137 seems to play a role in the induction of immune tolerance or immunosuppression . considering that cd137 signaling is critical in the induction of inflammation , blocking of cd137 signaling should inhibit the progression of inflammatory diseases . however , it should be careful in interpreting data that come from experiments performed in the absence of cd137 signals ( 28 ) . cd137l is expressed in apcs and other myeloid cells ( b cells , macrophages , dendritic cells , mast cells , and eosinophils ) and non - hematopoietic cells ( endothelial cells , fibroblasts , and epithelial cells ) ( 26 ) . evidence supporting that cd137l signals play an in vivo physiological role in inflammation is just being emerged , even though accumulating evidence has demonstrated the existence of cd137l signals at molecular and cellular levels . for example , cd137l signaling mediates cellular functions ranging from cell differentiation , proliferation , and survival to the production of inflammatory mediators in a variety of cells ( 29 ) . it is now becoming clear that cd137l signaling is critical in multiple phases of inflammation . inflamed vessels express cd137 and cd137l and cd137l signaling in endothelial cells leads to the production of proinflammatory cytokines and chemokines ( 4,5 ) . further , cd137l signaling may facilitate transendothelial migration of leukocytes through upregulation of cell adhesion molecules on endothelial cells ( 4,5 ) . on the other hand , cd137l signaling increases the expression of cell adhesion molecules on monocytes and promotes their extravasation ( 23 ) . since endothelial cells express both cd137 and cd137l , cd137-cd137l interactions between endothelial cells and leukocytes may amplify inflammation such a way that endothelial cells induce sustained production of inflammatory mediators and prime leukocytes before they arrive at inflamed tissue territories . in the tissues , it seems that cd137l signaling in recruited leukocytes , residential cells and parenchymal cells also is critical in the amplification of inflammation . macrophages express cd137l on exposure to an inflammatory environment and produce high levels of proinflamatory cytokines and chemokines in response to cd137l signals ( 5,30,31 ) . in collaboration with other inflammatory inducers , cd137l signaling results in the production of inflammatory mediators in macrophages in a synergistic manner ( 32 ) , an indication that cd137l signaling is an amplifier of inflammation . it is noteworthy that cd137l can sustain tlr signaling by binding to tlrs without engagement of cd137 ( 31 ) . recently , we have identified a novel inflammatatory pathway involving cd137l signaling in epithelial cells ( 33 ) . in kidney ischemia - reperfusion injury , cd137 expressed on infiltrated nk cells stimulates cd137l in tubular epithelial cells to produce cxcr1 and 2 that are required for recruitment of neutrophils in the kidney . since kidney ischemia - reperfusion injury does not occur without nk cells or neutrophils , it is thought that the axis of nk cell - tubular epithelial cell - neutrophils is the major pathogenic pathway for kidney ischemia - reperfusion injury ( 34 ) . as mentioned above , cd137l signaling is indispensible for kidney ischemia - reperfusion injury ( 33 ) . considering that cd137l signaling is critical in inflammatory responses , it is predicted that milder inflammatory diseases will occur in the absence of cd137l signals . indeed , we have demonstrated that blocking of cd137l can inhibit inflammatory responses and prevent mortality in candida albicans - induced sepsis ( unpublished data ) . in this model , cd137 signaling enhances the phagocytic activity of neutrophils , whereas cd137l signaling induces massive cytokine production by macrophages following candida albicans infection . in this model , agonistic anti - cd137 mab has dual beneficial effects on candida albicans - induced sepsis by promoting fungal clearance by neutrophils and downregulating cytokine production by macrophages . emerging evidence suggests that both cd137 and cd137l signals play an important role in the evolution of inflammation . cd137 signaling in lymphoid cells such as nk , nkt and t cells , promotes inflammation by producing ifn- and tnf-. however , the outcomes of cd137 signaling in regulatory t cells and neutrophils are connected to the suppression of inflammation . cd137 signaling in regulatory t cells and nk cells induces production of immunosuppressive cytokines that directly decrease inflammation ( unpublished result ) . cd137 signaling in neutrophils can facilitate pathogen clearance and thus contributes to rapid resolution of inflammation ( unpublished results ) .
although the majority of research on cd137 has been directed to t cells , it is becoming clear that this molecule has distinct functions in other lineages of cells , including non - hematopoietic cells . 
 in particular , emerging evidence suggests that the cd137-its ligand ( cd137l ) network involving immune cells and non - immune cells , directly or indirectly regulates inflammation in both positive and negative manners . 
 bidirectional signaling through both cd137 and cd137l is critical in the evolution of inflammation : 1 ) cd137l signaling plays an indispensible role in the activation and recruitment of neutrophils by inducing the production of proinflammatory cytokines and chemokines in hematopoietic and non - hematopoietic cells such as macrophages , endothelial cells and epithelial cells ; 2 ) cd137 signaling in nk cells and t cells is required for their activation and can influence other cells participating in inflammation via either their production of proinflammatory cytokines or engagement of cd137l by their cell surface cd137 : 3 ) cd137 signaling can suppress inflammation by controlling regulatory activities of dendritic cells and regulatory t cells . as recognition grows of the role of dysregulated cd137 or cd137l stimulation in inflammatory diseases , 
 significant efforts will be needed to develop antagonists to cd137 or cd137l .