inflammatory responses are defense mechanisms that protect the human body from microbial infection or external damage . the roman physician , celsus , is credited with providing the first record of the fundamental symptoms of inflammation , which are still recognized in modern textbooks . with recent advances in immunology , inflammatory responses are receiving new attention because of their involvement in the link between innate immunity and disease . stepping forward from classical concepts of the immune response ( i.e. the concept of self or non - self ) although autoimmune diseases can not be easily explained by the concept of self or non - self , they can be explained by the danger theory of inflammatory response . this theory could also be applied to understanding the inflammatory responses in the brain , where external intrusions are rare but immune / inflammatory responses occur , sometimes to a pathogenic degree ( i.e. in degenerative brain disease ) . neuroglial cells , including astrocytes and microglia , are the primary tissue - resident cells responsible for immune / inflammatory responses in the brain . if such responses are improperly regulated or terminated , nerve cell dysfunction can occur as a pathophysiology of brain disease . in this review , we outline a possible approach for targeting inflammatory responses in an effort to treat chronic inflammatory brain diseases . researchers studying inflammatory / immune processes in the brain must often refer to work done on peripheral inflammatory responses . because the endogenous stimulators of inflammatory / immune responses in the brain have not yet been clarified , researchers working with glial cells have looked to studies done in peripheral macrophages . to activate neuroglial cells , these researchers have used lipopolysaccharide ( lps ) and zymosan ( components of the bacterial cell wall and fungal cell membrane , respectively ) or inflammatory cytokines , including tumor necrosis factor ( tnf)- and interferon ( ifn)- ( well - known activators of peripheral macrophages ) . however , lps and zymosan rarely occur in the brain , making this model unsuitable for the study of brain pathophysiology . therefore , researchers have sought to identify endogenous substances that may be used as a model for brain disorders ( fig . two membrane components that are release from damaged nerve cells , gangliosides   and chromogranin , have been reported to cause inflammation and are currently being investigated as endogenous activating materials . many reports have shown the presence of long - term blood - brain barrier leakage in degenerative brain disease . based on these reports , researchers have hypothesized that components in the blood could intrude into the brain parenchyma and cause inflammation in the brain . efforts to identify inducers of neuroglial activation among blood components found that thrombin , prothrombin , plasminogen , and tissue plasminogen activator   can all activate neuroglial cells . aggregations of proteins ( e.g. prions , amyloid- and -synuclein ) , which are thought to be a common feature in alzheimer 's and parkinson 's diseases ( two typical degenerative brain diseases ) , have been identified as the main neuroglial cell - activating substances . in addition , intermittent hypoxia occurred in the brain is accompanied by oxidative stress and low - grade chronic inflammation , resulting in neurological deficits and disorders such as alzheimer 's and parkinson 's diseases . these recent studies have shown that inducers trigger inflammatory responses that can act as a major progression factor for ( if not a direct cause of ) degenerative diseases . thus , it seems reasonable to speculate that the regulation of inflammatory responses could prevent or slow disease progression . given that the endogenous stimulators of brain glial cells appear to trigger inflammation , we might next question which signaling pathways are activated by endogenous inflammatory stimulators in the brain . studies on the inflammatory signals in the brain have also drawn from work done in peripheral inflammatory cells . for example , nuclear factor - kappa b ( nf-b ) and mitogen - activated protein kinases ( mapks ) , two typical inflammatory signals , are reportedly activated in neuroglial cells by substances such as lps . moreover , endogenous stimulators , such as gangliosides   and thrombin , appear to cause inflammatory responses via nf-b and mapks . researchers are currently seeking to identify new inflammatory signaling molecules and pathways in the brain , in efforts to construct an activator- and cell type - specific roadmap . because the inflammatory signals are believed to have both shared and unique pathways according to the stimulus and/or tissue , researchers expect that a synergistic effect will be obtained by controlling the inflammatory signals or modulating their interactions . we identified janus kinase - signal transducer and activators of transcription ( jak - stat ) as a new inflammatory signal in the brain and showed that its inflammatory signals can be activated by lps , ifn- , gangliosides and thrombin . the receptor activated by these ligands or cytokines phosphorylates jaks , leading to the phosphorylation ( i.e. activation ) of stat molecules . activated stats form dimers and translocate to the nucleus , where they act as transcription factors ; they induce the expression of inflammatory genes that have stat - binding sites in their promoter regions , thereby activating subsequent inflammatory responses ( fig . signaling in brain inflammation , we screened anti - inflammatory substances to see if they could inhibit the jak - stat pathways , and if so , whether we could determine the underlying mechanism and identify a novel anti - inflammatory target . we found that curcumin ( which is a main ingredient of curries and has anti - inflammatory and anticancer effects ) , rosiglitazone ( an agonist for peroxisome proliferator - activated receptor  ; ppar ) and 15-deoxy - delta12,14-prostaglanding j2 ( 15d - pgj2 , an anti - inflammatory prostaglandin ) limit inflammation by inhibiting stat signaling . because the jak - stat pathways mediate the actions of numerous growth factors and cytokines in vivo , their negative feedback pathways are well developed and tightly regulated . the endogenous negative feedback molecules include phosphatases and inhibitory proteins , such as the suppressor of cytokine signaling ( socs ) proteins . curcumin activates sh2-containing phosphatase 2 ( shp2 ) , while rosiglitazone and 15d - pgj2 increase the expression levels of socs1 and socs3 . shp2 and socs proteins are typical negative feedback molecules of the jak - stat pathway . because the individual socs family proteins regulate different molecules of the jak - stat signaling pathways , we could possibly use them to specifically or synergistically control different jak - stat pathways . indeed , the anti - inflammatory properties of many clinically available drugs , including aspirin , are mediated via socs proteins . thus , it is particularly interesting to consider the development of additional socs - targeting drugs . steroids are representative anti - inflammatory drugs that act specifically through glucocorticoid receptors ( grs ) . despite the development of many new drugs , steroids are still broadly used to treat intractable diseases and pathological states , including inflammation , autoimmune disorders , and cancers . although steroids have demonstrated remarkable clinical efficacy , the exact mechanisms underlying such effects have only recently been unveiled . gr is a prototype ligand - activated transcription factor that belongs to the nuclear receptor ( nr ) family and regulates gene expression by either transcriptional activation   or transcriptional repression ( transrepression ) . in polysaccharide and lipid metabolism , steroid - activated gr forms a dimer , migrates into the nucleus and binds glucocorticoid response elements ( gres ) to induce target gene transcription . however , gres are absent from the promoter regions of most inflammatory genes , meaning that glucocorticoid - mediated anti - inflammation acts indirectly . indeed , the anti - inflammatory mechanism of steroids was found to act via transrepression , with ligand - activated gr indirectly suppressing the activity of inflammation - related transcription factors by inhibiting the binding of co - activators that promote transcription or by recruiting co - repressors to inhibit transcription . ppar and ppar , which are two typical nrs involved in lipid metabolism and adipocyte differentiation , are known to have anti - inflammatory actions . an anti - inflammatory effect has been reported for liver x receptor ( lxr ) . our group and other researchers showed that these nrs could exert anti - inflammatory effects in the central nervous system and peripheral inflammatory cells . moreover , post - translational modifications of nrs contribute to this process , leading to stimulus- and/or tissue - specific regulation of the inflammatory response . 3 ) . because most of the inflammatory mediators and cytokines that are activated by ifn- do not have lxr binding sites within their promoters , the inhibitory action of lxr results ( as in the case of gr ) from indirect action . although we showed that sumoylation of lxr plays a decisive role in tethering stat1 to lxr , the details of the underlying mechanism are still unknown . we are presently investigating whether the orphan nuclear receptor , short heterodimer partner ( shp ) , is involved in the lxr - dependent inhibition of stat1 transcriptional activity . shp lacks the conserved dna binding domain common to other nrs , suggesting that it may function by binding to other nrs . our preliminary results show that shp appears to mediate lxr - dependent stat1 inhibition ( unpublished data ) . the anti - inflammatory chemicals and drugs described above inhibit inflammatory signaling pathways or suppress the expression of inflammation mediator - encoding genes via transrepression . when tissues are damaged or infected by microbes , however , inflammatory mediators and cytokines should be released quickly and at high levels , requiring more efficient regulatory routes , such as through post - transcriptional alterations in their rna levels . many transcripts encoding pro - inflammatory cytokines and chemokines are present in an unstable state , undergoing rapid degradation due to the presence of au - rich elements ( ares ) in their 3'-untranslated regions ( 3'-utrs ) . the typical inflammatory genes that undergo regulation at the post - transcriptional step include cyclooxygenase-2 ( cox-2 ) , inducible nitric oxide synthase ( inos ) , tnf- , granulocyte - macrophage colony - stimulating factor ( gm - csf ) , interleukin-1 ( il-1 ) and ifn-. various rna - binding proteins and micrornas play important roles in the post - transcriptional regulation of mrna maturation , degradation , and translation . thus , these regulatory elements to control rna quality and quantity may also be viable targets for anti - inflammatory drugs . as researchers continue to study rna metabolism and uncover the detailed mechanisms underlying the creation and destruction of rna , other new potential anti - inflammatory drug targets may be identified . indeed , our group has shown that 5,8,11,14-eicosatetraynoic acid ( etya ) , 15d - pgj2   and 22(r)-hydroxycholesterol ( 22r - hc ) ( unpublished data ) suppress inflammation by altering the expression of makp phosphatase-1 ( mkp-1 ) , which dephosphorylates and inactivates jun n - terminal kinase ( jnk ) ( fig . 4 ) . these drugs increase the stability of the mkp-1 transcript in an hur - dependent manner , thereby increasing the protein expression of mkp-1 . interestingly , the mechanism through which mkp-1 expression is regulated differs by drug : in contrast to etya and 15d - pgj2 , dexamethasone ( a synthetic glucocorticoid ) increases mkp-1 expression by blocking its proteasomal protein degradation . we identified janus kinase - signal transducer and activators of transcription ( jak - stat ) as a new inflammatory signal in the brain and showed that its inflammatory signals can be activated by lps , ifn- , gangliosides and thrombin . the receptor activated by these ligands or cytokines phosphorylates jaks , leading to the phosphorylation ( i.e. activation ) of stat molecules . activated stats form dimers and translocate to the nucleus , where they act as transcription factors ; they induce the expression of inflammatory genes that have stat - binding sites in their promoter regions , thereby activating subsequent inflammatory responses ( fig . signaling in brain inflammation , we screened anti - inflammatory substances to see if they could inhibit the jak - stat pathways , and if so , whether we could determine the underlying mechanism and identify a novel anti - inflammatory target . we found that curcumin ( which is a main ingredient of curries and has anti - inflammatory and anticancer effects ) , rosiglitazone ( an agonist for peroxisome proliferator - activated receptor  ; ppar ) and 15-deoxy - delta12,14-prostaglanding j2 ( 15d - pgj2 , an anti - inflammatory prostaglandin ) limit inflammation by inhibiting stat signaling . because the jak - stat pathways mediate the actions of numerous growth factors and cytokines in vivo , their negative feedback pathways are well developed and tightly regulated . the endogenous negative feedback molecules include phosphatases and inhibitory proteins , such as the suppressor of cytokine signaling ( socs ) proteins . curcumin activates sh2-containing phosphatase 2 ( shp2 ) , while rosiglitazone and 15d - pgj2 increase the expression levels of socs1 and socs3 . shp2 and socs proteins are typical negative feedback molecules of the jak - stat pathway . because the individual socs family proteins regulate different molecules of the jak - stat signaling pathways , we could possibly use them to specifically or synergistically control different jak - stat pathways . indeed , the anti - inflammatory properties of many clinically available drugs , including aspirin , are mediated via socs proteins . thus , it is particularly interesting to consider the development of additional socs - targeting drugs . steroids are representative anti - inflammatory drugs that act specifically through glucocorticoid receptors ( grs ) . despite the development of many new drugs , steroids are still broadly used to treat intractable diseases and pathological states , including inflammation , autoimmune disorders , and cancers . although steroids have demonstrated remarkable clinical efficacy , the exact mechanisms underlying such effects have only recently been unveiled . gr is a prototype ligand - activated transcription factor that belongs to the nuclear receptor ( nr ) family and regulates gene expression by either transcriptional activation   or transcriptional repression ( transrepression ) . in polysaccharide and lipid metabolism , steroid - activated gr forms a dimer , migrates into the nucleus and binds glucocorticoid response elements ( gres ) to induce target gene transcription . however , gres are absent from the promoter regions of most inflammatory genes , meaning that glucocorticoid - mediated anti - inflammation acts indirectly . indeed , the anti - inflammatory mechanism of steroids was found to act via transrepression , with ligand - activated gr indirectly suppressing the activity of inflammation - related transcription factors by inhibiting the binding of co - activators that promote transcription or by recruiting co - repressors to inhibit transcription . ppar and ppar , which are two typical nrs involved in lipid metabolism and adipocyte differentiation , are known to have anti - inflammatory actions . an anti - inflammatory effect has been reported for liver x receptor ( lxr ) . our group and other researchers showed that these nrs could exert anti - inflammatory effects in the central nervous system and peripheral inflammatory cells . moreover , post - translational modifications of nrs contribute to this process , leading to stimulus- and/or tissue - specific regulation of the inflammatory response . 3 ) . because most of the inflammatory mediators and cytokines that are activated by ifn- do not have lxr binding sites within their promoters , the inhibitory action of lxr results ( as in the case of gr ) from indirect action . although we showed that sumoylation of lxr plays a decisive role in tethering stat1 to lxr , the details of the underlying mechanism are still unknown . we are presently investigating whether the orphan nuclear receptor , short heterodimer partner ( shp ) , is involved in the lxr - dependent inhibition of stat1 transcriptional activity . shp lacks the conserved dna binding domain common to other nrs , suggesting that it may function by binding to other nrs . our preliminary results show that shp appears to mediate lxr - dependent stat1 inhibition ( unpublished data ) . the anti - inflammatory chemicals and drugs described above inhibit inflammatory signaling pathways or suppress the expression of inflammation mediator - encoding genes via transrepression . when tissues are damaged or infected by microbes , however , inflammatory mediators and cytokines should be released quickly and at high levels , requiring more efficient regulatory routes , such as through post - transcriptional alterations in their rna levels . many transcripts encoding pro - inflammatory cytokines and chemokines are present in an unstable state , undergoing rapid degradation due to the presence of au - rich elements ( ares ) in their 3'-untranslated regions ( 3'-utrs ) . the typical inflammatory genes that undergo regulation at the post - transcriptional step include cyclooxygenase-2 ( cox-2 ) , inducible nitric oxide synthase ( inos ) , tnf- , granulocyte - macrophage colony - stimulating factor ( gm - csf ) , interleukin-1 ( il-1 ) and ifn-. various rna - binding proteins and micrornas play important roles in the post - transcriptional regulation of mrna maturation , degradation , and translation . thus , these regulatory elements to control rna quality and quantity may also be viable targets for anti - inflammatory drugs . as researchers continue to study rna metabolism and uncover the detailed mechanisms underlying the creation and destruction of rna , other new potential anti - inflammatory drug targets may be identified . indeed , our group has shown that 5,8,11,14-eicosatetraynoic acid ( etya ) , 15d - pgj2   and 22(r)-hydroxycholesterol ( 22r - hc ) ( unpublished data ) suppress inflammation by altering the expression of makp phosphatase-1 ( mkp-1 ) , which dephosphorylates and inactivates jun n - terminal kinase ( jnk ) ( fig . 4 ) . these drugs increase the stability of the mkp-1 transcript in an hur - dependent manner , thereby increasing the protein expression of mkp-1 . interestingly , the mechanism through which mkp-1 expression is regulated differs by drug : in contrast to etya and 15d - pgj2 , dexamethasone ( a synthetic glucocorticoid ) increases mkp-1 expression by blocking its proteasomal protein degradation . inflammation takes place in almost every tissue , and is designed to protect the body from microbial infection or external damage . to make use of it for therapeutic purposes for example , clinically available cox-2 inhibitors utilize the difference between cox isotypes to reduce the side effects on the gastrointestinal system , selectively inhibiting cox-2 while having less effect on cox-1 . most nrs are important transcription factors involved in metabolism , so any strategy to target them with anti - inflammatory drugs must preserve their effects on metabolism . for example , estrogen receptor inhibitors , which are used to treat breast cancer , were developed based on tissue - specific differences in estrogen receptor complex formation . these inhibitors selectively block the estrogen receptor in the mammary gland while having no effect on bone metabolism and minimizing adverse effects in tissues other than the mammary gland . the development of anti - inflammatory drugs targeting other nrs should take advantage of similar selectivity when possible . for example , the distribution of lxr isotypes differs between tissues : lxr is ubiquitously expressed at low levels in almost all tissues , while lxr is abundantly expressed in tissues involved in lipid metabolism and transport ( e.g. liver , intestine , lungs and adrenal glands ) . both lxr isoforms are expressed at significant levels in various regions of brain , with the level of lxr about 2- to 5-fold higher than that of lxr . thus , differences in tissue distribution could be used for tissue - specific control in the therapeutic context . similarly , tissue- and stimulus - specific differences in the compositions of nr complexes , which can determine the differential expression of target genes , could confer therapeutically relevant control . finally , selective control could potentially be achieved through alterations in the tissue- , stimulus- and target - gene - specific post - translational regulation ( e.g. sumoylation and glycosylation ) of various signaling pathway components . despite years of research , inflammatory responses and the mechanisms underlying the actions of anti - inflammatory drugs remain to be clarified . current studies in the field of immunology are expected to provide new insights into inflammation responses , inflammation - regulating drugs , and the relevant control mechanisms . some antibodies and drugs used in clinical practice are capable of directly targeting specific signaling molecules / receptors . in the case of anti - inflammatory drugs , detailed information is now being obtained regarding the pharmacological actions of typical non - steroidal anti - inflammatory drugs ( nsaids ) , such as aspirin and steroids . if we hope to effectively regulate inflammation for the treatment of diseases , the mechanism(s ) responsible for controlling the inflammatory response need to be firmly established . we should also seek to better understand the cause - and - effect relationships between inflammatory responses and the pathogenesis / progression of related human diseases . here , we reviewed the tissue- and stimulus - specific mechanisms believed to regulate inflammation , and discussed the need for new insights into their cause - and - effect relationships in the context of disease . given that inflammatory / immune responses are physiological phenomena that can provide protection or cause damage , their therapeutic modulation must be precisely controlled in quantitative , qualitative and temporal terms .
the term ' inflammation ' was first introduced by celsus almost 2000 years ago . 
 biological and medical researchers have shown increasing interest in inflammation over the past few decades , in part due to the emerging burden of chronic and degenerative diseases resulting from the increased longevity that has arisen thanks to modern medicine . 
 inflammation is believed to play critical roles in the pathogenesis of degenerative brain diseases , including alzheimer 's disease and parkinson 's disease . 
 accordingly , researchers have sought to combat such diseases by controlling inflammatory responses . in this review , 
 we describe the endogenous inflammatory stimulators and signaling pathways in the brain . 
 in particular , our group has focused on the jak - stat pathway , identifying anti - inflammatory targets and testing the effects of various anti - inflammatory drugs . 
 this work has shown that the jak - stat pathway and its downstream are negatively regulated by phosphatases ( shp2 and mkp-1 ) , inhibitory proteins ( socs1 and socs3 ) and a nuclear receptor ( lxr ) . 
 these negative regulators are controlled at various levels ( e.g. transcriptional , post - transcriptional and post - translational ) . 
 future study of these proteins could facilitate the manipulation of the inflammatory response , which plays ubiquitous , diverse and ambivalent roles under physiological and pathological conditions .