cytokines are small proteins initially thought to be components of the immune system , but have since been found to play a much broader role in physiology .
interleukin-6 ( il-6 ) is a cytokine originally identified as a b - cell differentiation factor ( bsf-2 ) in 1985 1 , as a factor that induced the maturation of b cells into antibody - producing cells .
human il-6 2 and il-6 receptor 3 were cloned soon thereafter . as with many other cytokines ,
it was soon realized that il-6 was not a factor only involved in the immune response . in early 1990s
it was clear that besides controlling other immune cells such as t cells , il-6 was also important in the regulation of hepatocytes , hematopoietic progenitor cells , the skeleton , the cardiovascular system , the placenta and the nervous and endocrine systems 4 .
structural analysis has allowed the grouping of these proteins into different structural classes such as the helical cytokines , the trimeric tumor necrosis factor ( tnf ) family , the cysteine knot growth factors and the -trefoil growth factors 5 .
cytokines can also be grouped according to the type of receptor they bind , which comprise six major families : class i cytokine receptors ( the largest family ) , class ii cytokine receptors , tnf receptors , tyrosine kinase receptors , and chemokine receptors 5 .
cytokine families may be named differently according to other aspects such as the sharing of a receptor subunit ( i.e. the gp130 family ) or its physiological roles ( i.e. neuropoietic family , for its effects on hematopoietic and nervous system ) .
il-6 is a prototypical four - helix bundle cytokine that is the founder member of the neuropoietins , a group of cytokines structurally related , that include il-6 , il-11 , il-27 , il-31 , leukemia inhibitory factor , oncostatin m , cardiotrophin-1 , neuropoietin and cytokine cardiotrophin - like ( also known as new neurotrophin 1 and b cell stimulatory factor-3 ) , and two viral analogs of il-6 5 - 10 .
these cytokines bind to class i cytokine receptors , membrane proteins with a characteristic modular architecture that do not have intrinsic enzymatic activity , and that for signaling often need to recruit additional receptor proteins shared by different cytokines : gp130 , c or c .
this protein has also a modular architecture , part of which has features typical of the cytokine receptors ( two fibronectin type iii modules containing conserved cysteine residues and a wsxws motif ) 4 . for il-6 specifically , a hexamer forms ( two il-6 , two il-6r and two gp130 ) that can activate intracellular tyrosin - kinases such as janus kinase ( jak ) and , to a lesser extent , tyk , which , in turn , activate a number of proteins including the stat ( signal transducer and activator of transcription ) family of transcription factors , or the ras - raf - mapk pathway , pi3 ( phosphatidyl inositol-3 ) kinase , or irs ( insulin receptor substrate ) 11 . the sharing of gp130 explains at least in part the redundancy of the actions of these cytokines .
it was soon established that the expression of il-6r is restricted to some tissues , while that of gp130 is ubiquitous , and that il-6 may upregulate gp130 expression 12 .
the same study already provided evidence that extracellular , soluble il-6r ( sil-6r ) in the presence of il-6 could activate cells expressing gp130 , and stated that naturally occurring sil-6r could be found in the murine serum .
it is now widely accepted that sil-6r is formed physiologically , either by limited proteolysis of the extracellular domain of membrane il-6r ( mil-6r ) by metalloproteases such as adam10 and adam17 , or by alternative splicing of il-6r mrna , and that sil-6r can bind both il-6 and gp130 and signal in cells with or without endogenous il-6r expression , a mechanism known as trans - signaling 13 . to complicate things further
, it is also known that a soluble form of gp130 ( sgp130 ) is also formed 14 , in this case only by alternative splicing of gp130 mrna ; sgp130 can inhibit trans - signaling but does not affect normal signaling by mil-6r ( figure 1 ) .
soon after its discovery , it was demonstrated that some astrocytoma and glioma lines expressed il-6 when stimulated with il-1 , which prompted speculation that il-6 could have a role in the cns 2 .
the same group demonstrated that il-6 indeed was capable of inducing the neuronal differentiation of the rat pheochromocytoma pc12 cell line , to some extent similarly to the prototypical neurotrophin ngf 15 , 16 .
it was therefore not surprising the finding that both glial and neuronal cells expressed il-6 and il-6r to various degrees throughout the brain 17 - 24 . in vitro , microglia , astrocytes and the neuronal line n18 , but not oligodendrocytes , expressed il-6r 25 ; in vivo , nevertheless , oligodendrocytes may express il-6 and il-6r 26 .
also , il-6 and il-6r were expressed in sympathetic and sensory ganglia , predominantly in neurons 27 , as well as in adrenal chromaffin cells 28 , of adult rats . in line with these results , in vitro studies demonstrated that dissociated sympathetic neurons and pc12 cells expressed il-6 and the two receptors , il-6r and gp130 29 , 30 .
besides neurons and glial cells , endothelial cells produce copious amounts of il-6 , which can act on surrounding cells but also in an autocrine manner regulating a number of adhesion proteins but also il-6 synthesis , particularly in the presence of sil-6r 31 - 33 .
thus , both the central and the peripheral nervous system appear to express il-6 and the corresponding receptors ( figure 1 ) . many cytokines and inflammatory factors as well as neurotranmitters and neuropeptides have been shown to affect il-6 regulation in brain cells ; we will comment here some of them studied in in vitro assays . both virus - infected microglial cells and
il-1 and tnf induced il-6 in cultured cortical neurons 36 and astrocytes 37 , 38 , in the latter involving nfb 39 and the pkc pathway 40 .
it is likely that membrane depolarization is one of the main mechanisms for neuronal upregulation of il-6 , where ca currents ( such as those elicited by the glutamate agonist nmda ) and ca / calmodulin - dependent kinases are critical factors 43 , 44 . the major bacterial pathogen , lps , normally induces il-6 in both astrocytes and microglia 45 - 47 , but tnf- induces il-6 in astrocytes but not microglia 45 .
there may be species - specific effects since in human cells in vitro lps mostly affect microglia rather than astrocytes ( obtained from brains at second trimester of gestation ) regarding tnf , il-1 and il-6 production , although il-1 is a potent stimulator of il-6 production in astrocytes ( in microglia the 3 cytokines are upregulated ) 46 , 48 .
gm - csf stimulates microglial il-6 but not that of astrocyte 49 , whereas ifn- induces il-6 ( and no ) in the murine microglial cell line 6 - 3 50 ; this cytokine does not induce il-6 in astrocytes unless it is coincubated with il-1 37 .
il-6 production by astrocytes is subjected to autocrine regulation by il-6 , and the addition of sil-6r synergizes dramatically with il-1 and tnf to induce il-6 52 .
oncostatin m ( osm ) induced il-6 alone and synergized with tnf to induce il-6 52 .
il-17 functioned in a synergistic manner with il-6 ( + sil-6r ) to induce il-6 expression in astrocytes 53 .
norepinephrine , vasoactive intestinal peptide ( vip ) and pituitary adenylate cyclase activating polypeptide ( pacap38 ) stimulate il-6 in astrocytes , and may synergize with il-1 and tnf 54 - 56 ; in contrast any of these factors have a major effect in microglia 54 .
vip may induce il-6 through the pka pathway and independently of prostaglandins 57 , 58 .
prostaglandin e1 ( pge1 ) and pge2 , but not pgd2 and pgf2 alphae2 , induce il-6 in human astrocytoma cells ; pge2 potentiates il-1 induction of il-6 59 , 60 .
the synthetic ceramides c2- and c6-ceramide as well as the enzyme sphingomyelinase were able to induce il-6 in astrocytes 61 .
il-1 , substance p and histamine induced il-6 expression in human astrocytoma cells 41 , 62 , through nf-b for il-1 and through nf - il-6 for sp and histamine 63 .
serotonin and adenosine agonists were also effective inducers in human astrocytoma cells 65 
 66 ; in mouse astrocytes , adenosine induces il-6 through activation of pka and nf - il-6 67 .
tgf- inhibits microglia proliferation and activation , including il-6 production 68 ; in contrast , it stimulates il-6 production in astrocytes 69 .
il-6 may affect neuronal functionality , for instance it induces the cholinergic phenotype of sympathetic neurons 30 , 70 , 71 .
sensory neurons are particularly affected by il-6 deficiency , since in normal conditions il-6 ko mice show a 60% reduction of the compound action potential of the sensory branch of the sciatic nerve and a dramatic decrease of temperature sensitivity in the frontpaw withdrawal time in the hot - plate assay 72 ; these neurons are also highly dependent on il-6 for functional recovery following injury 72 , 73 .
results with il-6 ko mice imply a role for il-6 on sympathetic sprouting induced by nerve injury 74 , 75 .
it also promotes sprouting and functional recovery of organotypical cultures of hippocampus 76 , and causes a dose - dependent decrease of post - tetanic potentiation ( ptp ) and long - term potentiation ( ltp ) in the ca1 region of rat hippocampus 77 .
il-6 also has a notorious role in adult neurogenesis 10 , 78 , the process of creating new neurons and glial cells from neural stem cells ( nscs ) discovered almost 50 years ago 79 , which is now known to be dramatically affected by a myriad of factors such as exercise , environmental enrichment , stress , or aging . not surprisingly , neurogenesis is also altered in many neuropathological situations like stroke , status epilepticus , mechanical damage , and alzheimer , parkinson and huntington diseases ; in all these cases a detrimental role of inflammation has usually been suggested 80 , 81 , and , as stated above , il-6 will be upregulated and could have a role on neurogenesis .
gfap - il6 mice , indeed , show a diminished hippocampal neurogenesis 82 , and moreover , in vitro il-6 clearly decreases the differentiation of neural stem / progenitor cells into neurons 83 , 84 .
in contrast , il-6 is involved in oligodendrogliogenesis 85 , 86 and astrogliogenesis 84 . yet , other studies claimed that il-6 promotes both gliogenesis ( through the stat-3 pathway ) and neurogenesis ( mapk / creb pathway ) 87 , 88 . besides effects on neurons , il-6 also displays a number of effects in glial and endothelial cells . early in vitro assays showed that both virus - infected microglia and astrocytes secreted il6 , and that il-6 induced the secretion of the major neurotrophin ngf by the latter 34 . in vitro
there is some conflicting results whether or not il-6 does have proliferative effects on astrocytes 89 , 90 , probably it does but synergizing with other factors 91 .
microglia in culture consistently proliferate when stimulated with il-6 92il-6-il-6/sil-6r may alter the factors produced by astrocytes : for instance it induces specific patterns of neurotrophins 93 , inhibits tnf 94 , and together with sil-6r and il-17 , it may shift chemokine production to that favoring t cell recruitment to the cns 95 .
differences in the pattern of cytokines secreted by astrocytes of il-6 ko mice are readily noticeable in vitro 96 . in vivo experiments demonstrate that il-6 exerts profound effects on their differentiation , which is dependent on the brain area from which they are isolated 93 .
transgenic mice overexpressing il-6 show prominent astrogliosis and microgliosis 97 - 100 , whereas the opposite is usually observed in il-6 ko mice in different models of injury 101 - 105 .
il-6 alone does not affect intercellular adhesion molecule-1 ( icam-1 ) gene expression , but dramatically inhibits the activating effect of ifn- , il-1 and tnf in rat astrocytes , and that of ifn- in microglia , very much alike il-10 106 .
in human astrocytes , il-6 , sil-6r or both do not affect vcam-1 or icam-1 , but il-6/sil-6r complex ( and h - il-6 ) inhibits tnf--induced vcam-1 gene expression ; sil-6r upregulates endogenous il-6 production 107 .
this inhibitory effect of il-6 in astrocytes is in sharp contrast with the stimulatory effect it has on endothelial cells , where again sil-6r greatly affects the activation of endothelial cells , not only upregulating the adhesion proteins e - selectin , icam-1 and vcam-1 but also il-6 , il-8 and monocyte chemotactic protein 1 ( mcp-1 ) ; this constitutes a model where neutrophils may retrogradely signal inflammation to endothelial cells by shedding sil-6r , which can then recruit leukocytes and contribute to their extravasation 32 , 108 . regarding oligodendrocytes , in addition to promoting oligondendrogenesis il-6 promotes survival and myelin production of oligodendrocytes 85 , 86 , 109 , 110 .
although il-6 is often related to inflammatory and pathological situations , it is a factor that contributes decisively in the normal function of the brain .
thus , il-6 is involved in the control of body weight , food intake and energy expenditure 111 - 115 , stimulates the pituitary - adrenal axis 116 
 117 , induces fever 111 , 118 , 119 and is for instance very important in the control of body temperature following recovery from stroke 120 .
results with il-6 ko mice imply a facilitatory role for il-6 in pain 74 , 75 , effects on sleep - wake beavior 121 , emotional reactivity 122 , 123 , sickness behaviour 124 and learning and memory 125 - 127 .
as stated above , soon after its discovery il-6 was shown to induce the neuronal differentiation of pc12 cells 15 , 16 .
after these initial studies , a flurry of papers demonstrated that il-6 affected in many different ways neurons and glial cells .
thus , it was shown to promote the survival of cultured basal forebrain and septal cholinergic neurons and mesencephalic catecholaminergic neurons 128 , 129 , retinal ganglion cells 130 , sympathetic neurons and dorsal root ganglia ( drg ) , particularly if sil-6r was added to the culture 30 , 131 .
it has been suggested that a survival mechanism could be the inhibition of neuronal activity and release of glutamate 132 . in vivo ,
il-6 increases with development in drg , but levels are low in adults ; however , following sciatic nerve transection its expression increases dramatically , not only in the drg but also in many neurons in the corresponding motor nucleus or sympathetic ganglion 133 .
studies in a drop weight model of cortex lesion ( closed skull ) also indicate that il-6 expression increases following axonal damage , mainly in neurons 134 , thus probably neuronal induction of il-6 in response to injury is a general response . in the sciatic model ,
il-6 expression increases potently within large and medium - sized axotomized neurons 133 , whose survival is decreased by 50% in il-6 ko mice 135 .
il-6 probably promotes survival through inducing bdnf , and indeed in vivo il-6 ko mice do not upregulate this neurotrophin in drg following nerve injury 136 .
experiments after injury of the hypoglossal nerve in mice also demonstrated a nerve regenerating role of il-6 137 .
in contrast , in the facial nerve axotomy model no difference in neuronal survival was observed 104 , whereas il-6 was shown to be detrimental in a model of optic nerve injury 138 .
cns il-6 is upregulated whenever neuroinflammation is expected , such as following cns infection or injury or in a number of cns diseases ( figures 2 and 3 ) .
early studies demonstrated that il-6 was expressed and produced in cns during viral meningitis , in encephalitis mouse models , and in csf of patients with acute viral infections 139 .
il-6 was also found to be upregulated in mouse experimental cerebral malaria ( ecm ) 140 .
moreover , il-6 was highly found in csf of patients with systemic lupus erithematosus ( sle ) with cns involvement 141 or in those in advanced stages of patients with human immunodeficiency virus 142 infections 143 .
il-6 levels in csf were also significantly higher than plasma levels in patients who had suffered traumatic brain injury 144 , and recently an il-6 polymorphism ( -174c / g ) has been associated with fatal outcome in patients with severe traumatic brain injury 145 .
as expected , il-6 is upregulated in several animal models of brain injury and shows a myriad of actions as suggested by studies in il-6 ko mice which show a compromised inflammatory response , increased oxidative stress , impaired neuroglial activation , decreased lymphocyte recruitment and a slower rate of recovery and healing 47 , 101 , 102 , 104 , 134 , 146 - 148 .
of note , il-6 is a critical cytokine controlling the transition from innate to acquired immunity , which is imperative for dealing properly with injured ( and infected ) cns tissue , and where il-6 trans - signalling is dramatically important 149 . in line with
the results with il-6 ko mice , gfap - il-6 mice ( which overexpress il-6 in the cns ) showed more rapid healing and recovery after traumatic brain injury because of extensive revascularization 148 , 150 .
the transcriptomic analysis of il-6ko mice versus wt mice 151 and that of gfap - il-6 mice 152 in a model of brain cortex cryoinjury revealed that il-6 modulates the expression of many genes involved in inflammation , apoptosis and oxidative stress among others .
stroke patients also show significant elevations of csf and serum il-6 shortly after the ischemic event that correlate with brain infarct volume , and il-6 haplotype affects both infarct size and il-6 levels 153 - 157 .
ischemic brain injury involves inflammation , excitotoxicity , oxidative damage and apoptosis , and thus to some extent it is a similar scenario as that following traumatic brain injury .
it is therefore not surprising that il-6 may be an important factor orchestrating the responses elicited by stroke . in animal models of cerebral ischemia
it has been a consistent finding an upregulation of il-6 , mostly in neurons but also in glial cells and vascular endothelium 158 - 161 . in line with the in vitro studies detailed above , neuronal il-6 upregulation following cerebral ischemia is likely mediated by glutamate - induced neuronal depolarization 44 , 162 , 163 .
several of these studies clearly demonstrated a neuroprotective role of exogenously administered il-6 , as did experiments injecting anti - mouse il-6 receptor monoclonal antibody 164 and with il-6 ko mice provided body temperature is controlled 120 , 165 . controlling oxidative stress 166 and angiogenesis 165 are among the attributed functions of il-6 during stroke .
epileptic seizures often involve excitotoxicity , and thus it was expected to find that patients suffering of epilepsy show increased csf levels of il-6 after seizures 167 , and that well - known animal models of epilepsy such as the glutamate analog kainic acid ( ka ) upregulate cns il-6 162 .
il-6 ko mice are more susceptible to various convulsant stimuli including several glutamate analogs and show clear signs of increased hippocampal damage 168 - 170 .
yet , this is a complex system , since intranasal administration of il-6 to rats 171 and transgenic il-6 expression in the brain 172 are proconvulsive .
also , some authors also claim a damaging role of il-6 on neuron development in culture and on the response to nmda 173 
 174 .
the reasons for such dual effects of il-6 remain uncertain , but probably reflect that the context has a dramatic effect as often is the case with growth factors . as a prototypical cytokine with roles in the control of inflammation , il-6
it is therefore not surprising that il-6 expression is altered in the brains of alzheimer 's disease ( ad ) patients , being increased around amyloid plaques and in cerebrospinal fluid 175 - 179 .
il-6 stimulated the synthesis of the ad beta - amyloid precursor protein 180 , 181 , and , conversely , il-6 is upregulated in cultured glial cells upon stimulation with the carboxy - terminal 105 amino acids of app 182 .
moreover , il-6 also enhances neuronal damage induced by beta - amyloid peptide in cultured rat cortical neurons 174 . despite this detrimental role of il-6 seen in vitro , in vivo studies with ad transgenic mouse models
rather show a beneficial role of il-6 , in principle due to a massive gliosis which attenuated beta - amyloid peptide deposition and enhanced plaque clearance 183 .
this is not unexpected as activated microglia can efficiently phagocytize beta - amyloid peptide and delay pathology course in transgenic models 184 - 186 .
astrocytes also may be involved in the clearance of beta - amyloid peptide 187 , also by regulating microglial phagocytosis 188 . in humans , attempts to find important interactions between polymorphisms in specific alleles , such as the il-6 - 174 g / c promoter allele , and genotype frequencies , are not conclusive 189 - 191 .
the -572c / g polymorphism of il-6 gene promoter region is another polymorphism that might be associated with ad 192 .
multiple sclerosis ( ms ) is an inflammatory demyelinating autoimmune disease of cns mediated by cd4+t cells and soluble inflammatory mediators , in which il-6 has an important role .
while there is significant controversy on whether or not ms is correlated with either plasma or csf il-6 , sil6r and sgp130 levels 193 - 196 , it has been demonstrated the presence of il-6 in acute and chronic active plaques of ms patients , mainly associated with astrocytes rather than macrophages or mononuclear infiltrating cells 197 . yet , the association of ms with il-6 polymorphisms is again not conclusive 198 , 199 .
one of the most common animal model of ms is experimental autoimmune encephalomyelitis ( eae ) 200 .
il-6 is upregulated in cns during eae 201 , and different approaches have demonstrated a major role of this cytokine .
thus , it was soon established that neutralization of il-6 with antibodies led to a reduced disease 202 , which later on was seen to be due to the suppression of the mog - induced differentiation of naive t cells into th17 and th1 cells 203 .
a seminal series of early studies demonstrated that il-6 deficient mice were resistant to eae 204 - 207 , highlighting the essential role of this cytokine .
absence of infiltrating cells in the cns , reduction of lymphocyte proliferation , change of the cytokine profile and failure to stimulate endothelial vcam-1 were some of the reasons suggested to be responsible for resistance to eae at the time .
trans - signaling is also crucial for eae induction as its blockade with gp130-fc fusion protein delayed the onset of adoptively transferred eae compared to controls due to a reduction in vcam-1 expression on spinal cord microvessels 208 . since the discovery of two novel subsets of t helper cells , named treg and th17 cells , and its importance in ms , it has been shown that il-6 has a major role in th17 cell differentiation from naive cd4 t cells , particularly in the eae model 203 , 209 , 210 .
th17 cells produce il-17 ( among other cytokines ) which enhances il-6 production by astrocytes , which in turn induces differentiation of th17 cells in a positive feedback loop between il-17 and il-6 53 , 211 .
although eae is considered a disease mostly induced peripherally , the fact is that the cns local milieu may have dramatic effects .
thus , the gfap - il6 mouse model of chronic transgenic il-6 expression 97 presents an atypical eae due to a retargeting of the immune attack , with no signs of spinal cord damage while showing a prominent cerebellar damage 212 .
the mechanisms responsible for these responses to il-6 in the cerebellum are complex and likely to include an increased vascular activation , loss of integrity of the bbb and the induction of specific cytokines and chemokines .
parkinson 's disease ( pd ) is a degenerative disorder of the cns with severe motor impairment , like shaking or rigidity among many others , due to the death of dopaminergic neurons in the substantia nigra .
il-6 is upregulated in pd 213 , 214 , and il-6 levels in the csf of pd patients are elevated 215 , although an inverse correlation between severity of pd and il-6 levels is observed 216 .
il-6 ko mice show increased vulnerability to the mptp , a molecule that is metabolized into the complex i inhibitor mpp+ by astrocytes and is a selective dopaminergic toxin 217 , whereas il-6 is capable of protecting rat dopaminergic neurons from the neurotoxicity of mpp 
 218 .
altogether , the results with these animal models of pd suggest that il-6 could be exerting a neuroprotective role during pd .
huntington 's disease 208 is an inherited neurodegenerative disorder with both neurological and systemic abnormalities , characterized by abnormalities in the huntingtin gene .
il-6 expression is dramatically elevated in the striatum of hd patients , and in general these patients show clear signs of abnormal immune activation , il-6 being one of the cytokines affected and monocytes , macrophages and microglia ( from both hd and mouse hd models ) being overactive upon stimulation 219 .
il-6 is suggested to be neuroprotective as concluded from results with the quinolonic acid rat model of hd 220 .
some studies have pointed out that il-6 levels in csf but not in plasma were increased in combat veterans with posttraumatic stress disorder ( ptsd ) in comparison with those of controls 223 , and that il-6 and/or sil-6r levels in plasma but not sgp130 were significantly higher in ptsd patients respect to controls , and higher in ptsd patients with concurrent major depression than in ptsd patients or controls 224 .
il-6 has also been related with schizophrenia ( sz ) , a complex neurological disorder characterized by a breakdown of thought processes and by poor emotional responsiveness , commonly manifested with hallucinations , delusions , paranoid and mental deterioration 225 , 226 .
thus , a single maternal injection of il-6 during pregnancy causes schizophrenia - like behavioral abnormalities in wt mice but not in il-6 ko mice 227 .
finally , il-6 has been found to be increased in the cerebellum of autistic brain 228 and has been suggested to mediate autism - like behaviors 229 .
many of its effects are caused by trans - signaling , while others are mediated by the membrane receptor ; both can be essentially considered an integrated , unique system .
the relevance of trans - signaling in vivo in a number of peripheral and cns diseases is widely recognized 111 , 149 , 230 - 234 , and not surprisingly therapeutic approaches aiming to counteract il-6 effects not only focus in il-6 membrane receptor 235 - 238 but also in il-6/sil-6r complex 13 , 239 - 241 . likewise , sgp130 is also of an invaluable utility to specifically block diseases states in which trans - signaling responses exist 232 , 234 , 241 , to the extent that the molecule has recently been structurally - optimized to better antagonize trans - signaling pathologic effects 242 .
still , we must keep in mind that il-6 has a role in the normal brain , and interfering with them may be a significant source of concern .
finally , we need to understand in vivo what the role(s ) of il-6 are to be due to specific cellular production of and response to il-6 ; hopefully the production of floxed mice for il-6 will help to answer these questions .
 interleukin-6 ( il-6 ) is a cytokine originally identified almost 30 years ago as a b - cell differentiation factor , capable of inducing the maturation of b cells into antibody - producing cells . as with many other cytokines , 
 it was soon realized that il-6 was not a factor only involved in the immune response , but with many critical roles in major physiological systems including the nervous system . 
 il-6 is now known to participate in neurogenesis ( influencing both neurons and glial cells ) , and in the response of mature neurons and glial cells in normal conditions and following a wide arrange of injury models . in many respects 
 , il-6 behaves in a neurotrophin - like fashion , and seemingly makes understandable why the cytokine family that it belongs to is known as neuropoietins . 
 its expression is affected in several of the main brain diseases , and animal models strongly suggest that il-6 could have a role in the observed neuropathology and that therefore it is a clear target of strategic therapies . 