HUGO ID Detailed Result 6014

HUGO ID 6014
Symbol IL4
Name interleukin 4
#Occurrence 236
#Paper 10

 

PMID Match String Actual String Score Flanking text Edited by Edit
12124437IL4IL40.3Contrastingly T-cell derived cytokines (lymphokines) lymphokines including IL2 IL3 and IL4 were detected at low levels in non-transgenic mice 
12124437IL4IL40.3Contrastingly T-cell derived cytokines (lymphokines) lymphokines including IL2 IL3 and IL4 were detected at low levels in non-transgenic mice but these 
15081582IL-4IL-41.3achieved by factors that inhibit NF-_amp_#x3ba B activity such as IL-4 IL-10 and IL-13 and glucocorticoids ( O'Banion 1999 (see see 
15210305IL4IL40.3120 days whereas T-cell derived cytokines (lymphokines) lymphokines including IL2 IL3 and IL4 are not differentially expressed at these time points 
15210305IL4IL40.3whereas T-cell derived cytokines (lymphokines) lymphokines including IL2 IL3 and IL4 are not differentially expressed at these time points 
16647138IL-4IL-41.3Thus factors that inhibit NF-_amp_#x3ba B activity such as IL-4 IL-10 and IL-13 can specifically inhibit COX-2 upregulation 
16753239IL-4IL-41.0Additionally this agonist suppressed IFN-_amp_#x3b3 IL-10 and IL-4 production by activated lymphocytes ( Diab et al. 2002 
17018025IL-4IL-42.7the neuroprotective mechanism of anti-inflammatory cytokines we applied interleukin-4 (IL-4) IL-4 to primary microglial cultures activated by lipopolysaccharide as well as 
17018025IL-4IL-42.7IL_amp_#8722 4 interaction with microglial IL-4 receptors suppressed and nitric oxide release and lessened lipopolysaccharide-induced microglia-mediated 
17018025IL-4IL-42.7Although IL-4 enhanced release of free IGF-1 from microglia in the absence 
17018025IL-4IL-42.7These data suggest that IL-4 may provide a significant immunomodulatory signal which can protect against 
17018025IL-4IL-42.7We hypothesized that the Th2 lymphocyte-derived anti-inflammatory cytokine interleukin-4 (IL-4) IL-4 may be one of the potential neuroprotective signals 
17018025IL-4IL-42.7IL-4 is an important immunosuppressive mediator in the CNS 
17018025IL-4IL-42.7IL-4 has also been shown to reduce the production of pro-inflammatory 
17018025IL-4IL-42.7Recently it has been documented that protection of IL-4 was attributed to down-regulation of TNF-A and up-regulation of insulin-like 
17018025IL-4IL-42.7In the present study we examined the effects of IL-4 in primary microglia cultures and in microglia cocultured with primary 
17018025IL-4IL-42.7The addition of IL-4 protected against the activated microglia-mediated motoneuron injury by reducing nitric 
17018025IL-4IL-42.7IL-4 additions were made either 2 h prior to or after 
17018025IL-4IL-42.7added to culture medium 1 h after the addition of IL-4 and lipopolysaccharide 
17018025IL-4IL-42.7treated with lipopolysaccharide (1 1 ng/mL) ng mL followed by IL-4 (10 10 ng/mL) ng mL 2 h later 
17018025IL-4IL-42.7U/mL), U mL lipopolysaccharide (1 1 ng/mL), ng mL and IL-4 (10 10 ng/mL) ng mL in HBSS were then added 
17018025IL-4IL-42.7IL-4 protected motoneurons from injury induced by activated microglia To determine 
17018025IL-4IL-42.7injury induced by activated microglia To determine the effects of IL-4 on microglia-mediated motoneuron injury IL-4 was added to MN Mc 
17018025IL-4IL-42.7To determine the effects of IL-4 on microglia-mediated motoneuron injury IL-4 was added to MN Mc cocultures 2 h before the 
17018025IL-4IL-42.7In the presence of IL-4 (10 10 ng/mL), ng mL neurite length (92.8% 92.8% _amp_plusmn 
17018025IL-4IL-42.7of nitrite nitrate increased after 24-h treatment with lipopolysaccharide and IL-4 significantly reduced nitric oxide production even in the presence of 
17018025IL-4IL-42.7Addition of IL-4 1-10 ng/mL ng mL significantly prevented motoneuron loss induced by 
17018025IL-4IL-42.7This protective effect of IL-4 was dose-dependent ( Fig 3d 
17018025IL-4IL-42.7With increasing concentrations of IL-4 nitrite nitrate levels in the supernatant decreased ( Fig 3e 
17018025IL-4IL-42.7To test whether IL-4 has any survival effects on motoneurons alone motoneurons were treated 
17018025IL-4IL-42.7any survival effects on motoneurons alone motoneurons were treated with IL-4 (10 10 ng/mL) ng mL for 48 h 
17018025IL-4IL-42.7The survival of motoneurons with IL-4 (99.93 99.93 _amp_plusmn 2.48% was similar to survival of motoneurons 
17018025IL-4IL-42.7was similar to survival of motoneurons in the absence of IL-4 (100% 100% as control 
17018025IL-4IL-42.7Therefore IL-4 had no direct survival effects on motoneurons supporting that the 
17018025IL-4IL-42.7survival effects on motoneurons supporting that the neuroprotective effects of IL-4 in microglia-motoneuron cocultures are mediated indirectly through microglia 
17018025IL-4IL-42.7Nitric oxide was a key factor modulated by IL-4 
17018025IL-4IL-42.7To provide further evidence that the neuroprotective effects of IL-4 may be mediated by reducing nitric oxide production we plotted 
17018025IL-4IL-42.7we plotted the nitrite nitrate content at different concentrations of IL-4 
17018025IL-4IL-42.7treated with lipopolysaccharide the suppression of nitrite nitrate generation by IL-4 was dose-dependent ( Fig 4a 
17018025IL-4IL-42.7To further define the mechanisms of IL-4 neuroprotection microglia were treated with lipopolysaccharide in the presence or 
17018025IL-4IL-42.7were treated with lipopolysaccharide in the presence or absence of IL-4 
17018025IL-4IL-42.7Figure 5 demonstrates that lipopolysaccharide enhanced iNOS protein expression and IL-4 significantly inhibited iNOS expression induced by lipopolysaccharide 
17018025IL-4IL-42.7Most strikingly the inhibitory effect of IL-4 added 2 h after lipopolysaccharide (lipopolysaccharide lipopolysaccharide IL-4 was even 
17018025IL-4IL-42.7effect of IL-4 added 2 h after lipopolysaccharide (lipopolysaccharide lipopolysaccharide IL-4 was even greater than when IL-4 was added 2 h 
17018025IL-4IL-42.7after lipopolysaccharide (lipopolysaccharide lipopolysaccharide IL-4 was even greater than when IL-4 was added 2 h before lipopolysaccharide (IL-4 IL-4 lipopolysaccharide ( 
17018025IL-4IL-42.7than when IL-4 was added 2 h before lipopolysaccharide (IL-4 IL-4 lipopolysaccharide ( p _lt_ 0.05 
17018025IL-4IL-42.7IL-4 receptor was up-regulated by lipopolysaccharide and IL-4-mediated neuroprotection was increased 
17018025IL-4IL-4-mediated1.3IL-4 receptor was up-regulated by lipopolysaccharide and IL-4-mediated neuroprotection was increased To help explain why IL-4 was more 
17018025IL-4IL-42.7lipopolysaccharide and IL-4-mediated neuroprotection was increased To help explain why IL-4 was more effective when added after lipopolysaccharide (lipopolysaccharide lipopolysaccharide IL-4 
17018025IL-4IL-42.7IL-4 was more effective when added after lipopolysaccharide (lipopolysaccharide lipopolysaccharide IL-4 expression of IL-4 receptor (IL-4R) IL-4R was assayed by real-time 
17018025IL-4IL-42.7effective when added after lipopolysaccharide (lipopolysaccharide lipopolysaccharide IL-4 expression of IL-4 receptor (IL-4R) IL-4R was assayed by real-time RT-PCR in microglia 
17018025IL-4IL-42.7provides a possible explanation for why adding lipopolysaccharide prior to IL-4 enhanced the protective effects of IL-4 
17018025IL-4IL-42.7adding lipopolysaccharide prior to IL-4 enhanced the protective effects of IL-4 
17018025IL-4IL-42.7In the absence of lipopolysaccharide IL-4 did not significantly change IL-4R mRNA levels compared with untreated 
17018025IL-4IL-42.7Furthermore IL-4R mRNA levels were not statistically changed by IL-4 in lipopolysaccharide-activated microglia (IL-4 IL-4 lipopolysaccharide compared with the group 
17018025IL-4IL-42.7were not statistically changed by IL-4 in lipopolysaccharide-activated microglia (IL-4 IL-4 lipopolysaccharide compared with the group treated with lipopolysaccharide only ( 
17018025IL-4IL-42.7Cultures treated with IL-4 2 h after the addition of lipopolysaccharide led to 104.6% 
17018025IL-4IL-42.7higher than the motoneuron survival (83.5% 83.5% _amp_plusmn 4.05 when IL-4 was added 2 h prior to the addition of lipopolysaccharide 
17018025IL-4IL-42.7IL-4 inhibited superoxide production from microglia The effect of the anti-inflammatory 
17018025IL-4IL-42.7IL-4 significantly suppressed the microglial release of in the presence of 
17018025IL-4IL-42.7release of in the presence of lipopolysaccharide (Mc Mc lipopolysaccharide IL-4 105.6% _amp_plusmn 24.5 vs Mc lipopolysaccharide 183.3% _amp_plusmn 11.8 p 
17018025IL-4IL-42.711.8 p = 0.005 and the level of Mc lipopolysaccharide IL-4 was not significantly different from control ( p = 0.79 
17018025IL-4IL-42.7Exogenous nitric oxide and reversed the neuroprotective effects of IL-4 To further prove that neuroprotective effects of IL-4 are through 
17018025IL-4IL-42.7effects of IL-4 To further prove that neuroprotective effects of IL-4 are through reducing nitric oxide and release from microglia exogenous 
17018025IL-4IL-42.7Figure 8 showed that in the presence of lipopolysaccharide and IL-4 addition of nitric oxide donor (NOC-18, NOC-18 25 _amp_#x03BC m 
17018025IL-4IL-42.7exogenous nitric oxide and could reverse the neuroprotective effects of IL-4 
17018025IL-4IL-42.7Free IGF-1 did not increase after addition of IL-4 to lipopolysaccharide-activated microglia In Fig 1b we noted less free 
17018025IL-4IL-42.7To determine whether IGF-1 production was influenced by IL-4 the levels of free IGF-1 were measured in microglia monocultures 
17018025IL-4IL-42.7In cultures without lipopolysaccharide IL-4 significantly increased levels of free IGF-1 ( Fig 9a b 
17018025IL-4IL-42.7close to background level in the presence or absence of IL-4 (data data not shown indicating that microglia were the source 
17018025IL-4IL-42.7microglia were the source of the increased free IGF-1 after IL-4 treatment 
17018025IL-4IL-42.7microglia or in MN Mc lipopolysaccharide cocultures regardless of whether IL-4 was added before or after lipopolysaccharide ( Fig 9a b 
17018025IL-4IL-42.7seen when IGF-1 mRNA levels were measured with and without IL-4 (data data not shown 
17018025IL-4IL-42.7The present study demonstrates that the anti-inflammatory cytokine IL-4 can protect motoneurons from injury induced by lipopolysaccharide-activated microglia 
17018025IL-4IL-42.7To our knowledge this is the first report that IL-4 has beneficial effects on motoneuron injury mediated by microglia 
17018025IL-4IL-42.7nitrite nitrate levels and motoneuron survival in cocultures treated with IL-4 and exogenously added nitric oxide reversed neuroprotection of IL-4 
17018025IL-4IL-42.7with IL-4 and exogenously added nitric oxide reversed neuroprotection of IL-4 
17018025IL-4IL-42.7suggest that nitric oxide is a key factor modulated by IL-4 in our cell culture system 
17018025IL-4IL-42.7by iNOS in microglia iNOS protein expression was down-regulated by IL-4 in activated microglia when IL-4 was given either before or 
17018025IL-4IL-42.7protein expression was down-regulated by IL-4 in activated microglia when IL-4 was given either before or after the triggering signal lipopolysaccharide 
17018025IL-4IL-42.7More strikingly we found that IL-4 increased motoneuron survival to a greater extent when added to 
17018025IL-4IL-42.7the cause of this increase we examined the levels of IL-4 mRNA 
17018025IL-4IL-42.7of IL-4R with the subsequent greater efficacy of the available IL-4 could provide one potential explanation of the increased suppressive effects 
17018025IL-4IL-42.7provide one potential explanation of the increased suppressive effects of IL-4 on iNOS expression in activated microglia 
17018025IL-4IL-42.7Two studies have reported the inhibitory effects of IL-4 on iNOS in lipopolysaccharide-stimulated astrocytes and mixed glial cultures ( 
17018025IL-4IL-42.7although in their studies the cells were all treated with IL-4 first and then stimulated cell with other triggering signals 
17018025IL-4IL-42.7Our present findings that IL-4 also inhibits production in lipopolysaccharide-activated microglia and that neuroprotection of 
17018025IL-4IL-42.7also inhibits production in lipopolysaccharide-activated microglia and that neuroprotection of IL-4 was reversed by exogenous illustrate another potential neuroprotective aspect of 
17018025IL-4IL-42.7(1995 1995 reported that IL-4 suppressed production in human microglia activated by TNF-A or interferon 
17018025IL-4IL-42.7It has been shown that IL-4 reduces formation in macrophages via down-regulation of gp9l-phox at the 
17018025IL-4IL-42.7The ability of IL-4 to suppress the production of both nitric oxide and suggests 
17018025IL-4IL-42.7suppress the production of both nitric oxide and suggests that IL-4 can decrease the formation of peroxynitrite 
17018025IL-4IL-42.7It has also been documented that neuroprotection of IL-4 was attributed to down-regulation of TNF-A ( Butovsky et al 
17018025IL-4IL-42.7TNF-A produced by microglia ( Zhao et al 2004 and IL-4 significantly decreased TNF-A levels in MN Mc lipopolysaccharide cocultures (data 
17018025IL-4IL-42.7Therefore down-regulation of TNF-A is one of mechanisms by which IL-4 inhibited nitric oxide and production and protected motoneurons from microglia-mediated 
17018025IL-4IL-42.7Another finding in the current study is that IL-4 increased free IGF-1 the active form of this neuroprotective factor 
17018025IL-4IL-42.7of free IGF-1 in microglia might be another aspect of IL-4 neuroprotection however our subsequent results suggested it might not be 
17018025IL-4IL-42.7IL-4 increased motoneuron survival in both lipopolysaccharide-treated MN Mc cocultures however 
17018025IL-4IL-42.7increased motoneuron survival in both lipopolysaccharide-treated MN Mc cocultures however IL-4 did not increase free IGF-1 levels in the same cocultures 
17018025IL-4IL-42.7in these lipopolysaccharide-activated cultures although it has been reported that IL-4 up-regulated IGF-1 mRNA in both untreated and lipopolysaccharide-activated microglia ( 
17018025IL-4IL-42.7Additionally even though free IGF-1 was up-regulated by IL-4 in untreated microglia cocultured with motoneurons IL-4 did not increase 
17018025IL-4IL-42.7was up-regulated by IL-4 in untreated microglia cocultured with motoneurons IL-4 did not increase motoneuron survival under the same conditions 
17018025IL-4IL-42.7suggest that IGF-1 may not be the primary mechanism of IL-4 neuroprotection 
17018025IL-4IL-42.7it is likely that the free IGF-1 levels induced by IL-4 either before or after lipopolysaccharide in our system were not 
17018025IL-4IL-42.7Several studies have demonstrated the beneficial effects of IL-4 in the CNS 
17018025IL-4IL-42.7(1993 1993 reported that IL-4 blocked microglia-mediated cerebral neuron injury 
17018025IL-4IL-42.7It has also been reported that IL-4 increased neuronal survival in hippocampal mixed cultures ( Araujo and 
17018025IL-4IL-42.7IL-4 delivered by transfected cells inhibited the progression and the severity 
17018025IL-4IL-42.7Furthermore gene transfer of IL-4 to the retina enhanced the survival of axotomized retinal ganglion 
17018025IL-4IL-42.7While these studies demonstrate that IL-4 can be neuroprotective few studies have examined the mechanisms of 
17018025IL-4IL-42.7Our present study provides evidence that IL-4 protects motoneurons from injury partly by decreasing free radicals released 
17018025IL-4IL-42.7Whereas one paper reported that IL-4 did not significantly suppress nitric oxide production from microglia when 
17018025IL-4IL-42.7and lipopolysaccharide ( Chao et al 1993 we found that IL-4 was more neuroprotective when added 2 h after lipopolysaccharide than 
17018025IL-4IL-42.7Besides IL-4 IL-10 and transforming growth factor-beta (TGF-B) TGF-B are two other 
17018025IL-4IL-42.7TGF-B in our MN Mc coculture system as well as IL-4 
17018025IL-4IL-42.7We found that IL-4 had stronger protective effects on motoneurons than IL-10 
17018025IL-4IL-42.7Like IL-4 IL-10 inhibited iNOS expression and nitric oxide production from microglia 
17018025IL-4IL-42.7One potential source of the neuroprotective signal IL-4 is Th2 lymphocytes 
17018025IL-4IL-42.7Our present data suggest that IL-4 may be one of the significant signals in T-cell-mediated neuroprotection 
17018025IL-4IL-42.7increase the presence of Th2 lymphocytes and the release of IL-4 would be a promising direction for treatment of neurodegenerative disorders 
17018025IL-4IL-42.7In vivo studies will clearly be required to determine whether IL-4 achieves neuroprotection by mitigating the neurotoxic effects of microglia 
17569578IL-4IL-41.315d-PGJ 2 inhibited T-cell proliferation and suppressed IFN_amp_#x3b3 IL-10 and IL-4 generation by activated lymphocytes 53 
17569578IL-4Il-41.3The authors showed that gemfibrozil and ciprofibrate induced Il-4 production in murine and human lymphocytes while IFN_amp_#x3b3 production was 
18464925IL-4IL-41.3diseases PPAR-_amp_#x003b3 has also been involved in anti-inflammatory functions of IL-4 a Th2 type cytokine which plays an important role in 
18464925IL-4IL-41.3and the increase of survival of differentiating OPs induced by IL-4 in inflammatory cytokine-stimulated mixed cultures are mediated by PPAR-_amp_#x003b3 activation 
18464925IL-4IL-4-induced1.3(12/15-LOX) 12 15-LOX in IL-4-treated glial cells and show that IL-4-induced PPAR-_amp_#x003b3 activation antagonizes NF-_amp_#x003ba B transactivation in inflammatory cytokine-stimulated astrocytes 
18464925IL-4IL-41.3A similar upregulation of PPAR-_amp_#x003b3 by IL-4 was demonstrated in cultured microglial cells 66 
18464925IL-4IL-41.3To link between IL-4 and PPAR-_amp_#x003b3 is completed by the observation that the anti-inflammatory 
18464925IL-4IL-41.3the TZD troglitazone was mediated by its ability to increase IL-4 expression in glial cultures 67 
11173059interleukin 4interleukin 41.0furthermore interleukin 2 interleukin 4 and interleukin 6 levels are elevated in the ventricular cerebrospinal fluid and in the caudate nucleus and putamen of patients with parkinson's disease hirsch 2000 .  
15081582il 4il 41.0specific inhibition of cox 2 upregulation can be achieved by factors that inhibit nf _amp_#x3ba;b activity such as il 4 il 10 and il 13 and glucocorticoids o'banion 1999 see table 1 .  
16647138il 4il 41.0thus factors that inhibit nf _amp_#x3ba;b activity such as il 4 il 10 and il 13 can specifically inhibit cox 2 upregulation.  
16753239il 4il 41.0additionally this agonist suppressed ifn _amp_#x3b3; il 10 and il 4 production by activated lymphocytes diab et al. 2002 .  
17018025interleukin 4interleukin 41.0to explore the neuroprotective mechanism of anti inflammatory cytokines we applied interleukin 4 il 4 to primary microglial cultures activated by lipopolysaccharide as well as to activated microglia cocultured with primary motoneurons. lipopolysaccharide increased nitric oxide and superoxide o 2 
17018025il 4il 41.0to explore the neuroprotective mechanism of anti inflammatory cytokines we applied interleukin 4 il 4 to primary microglial cultures activated by lipopolysaccharide as well as to activated microglia cocultured with primary motoneurons. lipopolysaccharide increased nitric oxide and superoxide o 2 _amp 
17018025il 4il 41.0il_amp_#8722;4 interaction with microglial il 4 receptors suppressed and nitric oxide release and lessened lipopolysaccharide induced microglia mediated motoneuron injury.  
17018025il 4il 41.0although il 4 enhanced release of free igf 1 from microglia in the absence of lipopolysaccharide it did not enhance free igf 1 release in the presence of lipopolysaccharide.  
17018025il 4il 41.0these data suggest that il 4 may provide a significant immunomodulatory signal which can protect against microglia mediated neurotoxicity by suppressing the production and release of free radicals.  
17018025interleukin 4interleukin 41.0we hypothesized that the th2 lymphocyte derived anti inflammatory cytokine interleukin 4 il 4 may be one of the potential neuroprotective signals.  
17018025il 4il 41.0we hypothesized that the th2 lymphocyte derived anti inflammatory cytokine interleukin 4 il 4 may be one of the potential neuroprotective signals.  
17018025il 4il 41.0il 4 is an important immunosuppressive mediator in the cns.  
17018025il 4il 41.0il 4 has also been shown to reduce the production of pro inflammatory cytokines such as il 6 il 8 tumor necrosis factor alpha tnf a mip 1a and rantes in glial cultures treated with lipopolysaccharide or i 
17018025il 4il 41.0recently it has been documented that protection of il 4 was attributed to down regulation of tnf a and up regulation of insulin like growth factor 1 igf 1 from microglia butovsky et al 2005 2006 .  
17018025il 4il 41.0in the present study we examined the effects of il 4 in primary microglia cultures and in microglia cocultured with primary motoneurons.  
17018025il 4il 41.0the addition of il 4 protected against the activated microglia mediated motoneuron injury by reducing nitric oxide production and suppressing microglial production.  
17018025il 4il 41.0il 4 additions were made either 2 h prior to or after the addition of lipopolysaccharide.  
17018025il 4il 41.0noc 18 nitric oxide donor and pyrogallol donor were added to culture medium 1 h after the addition of il 4 and lipopolysaccharide.  
17018025il 4il 41.0briefly microglia cultures 4 _amp_#x00d7; 10 4 cells/well grown in 96 well plates were treated with lipopolysaccharide 1 ng/ml followed by il 4 10 ng/ml 2 h later.  
17018025il 4il 41.0to each well ferricytochrome c 80 _amp_#x03bc; m catalase 10 u/ml lipopolysaccharide 1 ng/ml and il 4 10 ng/ml in hbss were then added.  
17018025il 4il 41.0il 4 protected motoneurons from injury induced by activated microglia to determine the effects of il 4 on microglia mediated motoneuron injury il 4 was added to mn + mc cocultures 2 h before the addition of lipopolysaccharide.  
17018025il 4il 41.0in the presence of il 4 10 ng/ml neurite length 92.8% _amp_plusmn; 7.82 increased significantly compared with mn + mc + lipopolysaccharide fig 3a b .  
17018025il 4il 41.0in coculture supernatants levels of nitrite + nitrate increased after 24 h treatment with lipopolysaccharide and il 4 significantly reduced nitric oxide production even in the presence of lipopolysaccharide fig 3c .  
17018025il 4il 41.0addition of il 4 1 10 ng/ml significantly prevented motoneuron loss induced by lipopolysaccharide activated microglia.  
17018025il 4il 41.0this protective effect of il 4 was dose dependent fig 3d .  
17018025il 4il 41.0with increasing concentrations of il 4 nitrite + nitrate levels in the supernatant decreased fig 3e and motoneuron survival increased fig 3d .  
17018025il 4il 41.0to test whether il 4 has any survival effects on motoneurons alone motoneurons were treated with il 4 10 ng/ml for 48 h.  
17018025il 4il 41.0the survival of motoneurons with il 4 99.93 _amp_plusmn; 2.48% was similar to survival of motoneurons in the absence of il 4 100% as control .  
17018025il 4il 41.0therefore il 4 had no direct survival effects on motoneurons supporting that the neuroprotective effects of il 4 in microglia motoneuron cocultures are mediated indirectly through microglia.  
17018025il 4il 41.0nitric oxide was a key factor modulated by il 4  
17018025il 4il 41.0to provide further evidence that the neuroprotective effects of il 4 may be mediated by reducing nitric oxide production we plotted the nitrite + nitrate content at different concentrations of il 4.  
17018025il 4il 41.0in mn + mc cocultures treated with lipopolysaccharide the suppression of nitrite + nitrate generation by il 4 was dose dependent fig 4a .  
17018025il 4il 41.0to further define the mechanisms of il 4 neuroprotection microglia were treated with lipopolysaccharide in the presence or absence of il 4.  
17018025il 4il 41.0figure 5 demonstrates that lipopolysaccharide enhanced inos protein expression and il 4 significantly inhibited inos expression induced by lipopolysaccharide.  
17018025il 4il 41.0most strikingly the inhibitory effect of il 4 added 2 h after lipopolysaccharide lipopolysaccharide + il 4 was even greater than when il 4 was added 2 h before lipopolysaccharide il 4 + lipopolysaccharide p _lt_ 0.05 .  
17018025il 4il 41.0il 4 receptor was up regulated by lipopolysaccharide and il 4 mediated neuroprotection was increased to help explain why il 4 was more effective when added after lipopolysaccharide lipopolysaccharide + il 4 expression of il 4 receptor il 4r was assayed by real time rt pcr in microglia cultures fig 6a .  
17018025il 4il 41.0 was more effective when added after lipopolysaccharide lipopolysaccharide + il 4 expression of il 4 receptor il 4r was assayed by real time rt pcr in microglia cultures fig 6a .  
17018025il 4il 41.0charide significantly increased the expression of il 4r compared with untreated microglia 9 fold increase p _lt_ 0.001 which provides a possible explanation for why adding lipopolysaccharide prior to il 4 enhanced the protective effects of il 4.  
17018025il 4il 41.0 enhanced the protective effects of il 4.  
17018025il 4il 41.0in the absence of lipopolysaccharide il 4 did not significantly change il 4r mrna levels compared with untreated control p = 0.91 .  
17018025il 4il 41.0furthermore il 4r mrna levels were not statistically changed by il 4 in lipopolysaccharide activated microglia il 4 + lipopolysaccharide compared with the group treated with lipopolysaccharide only p = 0.13 .  
17018025il 4il 41.0cultures treated with il 4 2 h after the addition of lipopolysaccharide led to 104.6% _amp_plusmn; 7.62 motoneuron survival which was significantly higher than the motoneuron survival 83.5% _amp_plusmn; 4.05 when il 4 was adde 
17018025il 4il 41.0 2 h after the addition of lipopolysaccharide led to 104.6% _amp_plusmn; 7.62 motoneuron survival which was significantly higher than the motoneuron survival 83.5% _amp_plusmn; 4.05 when il 4 was added 2 h prior to the addition of lipopolysaccharide fig 6b .  
17018025il 4il 41.0il 4 inhibited superoxide production from microglia the effect of the anti inflammatory cytokine on microglial production is shown in fig. 7 .  
17018025il 4il 41.0il 4 significantly suppressed the microglial release of in the presence of lipopolysaccharide mc + lipopolysaccharide + il 4: 105.6% _amp_plusmn; 24.5 vs mc + lipopolysaccharide 183.3% _amp_plusmn; 11.8 p = 0.005 and the level of mc + lipopolysaccharide + il 4 was not significantly different from control p = 0.79 .  
17018025il 4il 41.0: 105.6% _amp_plusmn; 24.5 vs mc + lipopolysaccharide 183.3% _amp_plusmn; 11.8 p = 0.005 and the level of mc + lipopolysaccharide + il 4 was not significantly different from control p = 0.79 .  
17018025il 4il 41.0exogenous nitric oxide and reversed the neuroprotective effects of il 4 to further prove that neuroprotective effects of il 4 are through reducing nitric oxide and release from microglia exogenous nitric oxide and were added to the motoneuron and microglia cocultures.  
17018025il 4il 41.0figure 8 showed that in the presence of lipopolysaccharide and il 4 addition of nitric oxide donor noc 18 25 _amp_#x03bc; m and donor pyrogallol pyr 30 _amp_#x03bc; m significantly decreased motoneuron survival to levels similar to those of mn + mc + lipopolysacchari 
17018025il 4il 41.0p_#x03bc; m significantly decreased motoneuron survival to levels similar to those of mn + mc + lipopolysaccharide showing that exogenous nitric oxide and could reverse the neuroprotective effects of il 4.  
17018025il 4il 41.0free igf 1 did not increase after addition of il 4 to lipopolysaccharide activated microglia in fig. 1b we noted less free igf 1 in the culture media following microglial activation with lipopolysaccharide.  
17018025il 4il 41.0to determine whether igf 1 production was influenced by il 4 the levels of free igf 1 were measured in microglia monocultures or mn + mc cocultures.  
17018025il 4il 41.0in cultures without lipopolysaccharide il 4 significantly increased levels of free igf 1 fig 9a b .  
17018025il 4il 41.0the free igf 1 of motoneuron only cultures were close to background level in the presence or absence of il 4 data not shown indicating that microglia were the source of the increased free igf 1 after il 4 treatment.  
17018025il 4il 41.0however the levels of free igf 1 did not change significantly in lipopolysaccharide activated microglia or in mn + mc + lipopolysaccharide cocultures regardless of whether il 4 was added before or after lipopolysaccharide fig 9a b .  
17018025il 4il 41.0similar results were seen when igf 1 mrna levels were measured with and without il 4 data not shown .  
17018025il 4il 41.0the present study demonstrates that the anti inflammatory cytokine il 4 can protect motoneurons from injury induced by lipopolysaccharide activated microglia.  
17018025il 4il 41.0to our knowledge this is the first report that il 4 has beneficial effects on motoneuron injury mediated by microglia.  
17018025il 4il 41.0our present results reveal a strong negative correlation between nitric oxide levels measured by nitrite + nitrate levels and motoneuron survival in cocultures treated with il 4 and exogenously added nitric oxide reversed neuroprotection of il 4.  
17018025il 4il 41.0 and exogenously added nitric oxide reversed neuroprotection of il 4.  
17018025il 4il 41.0these suggest that nitric oxide is a key factor modulated by il 4 in our cell culture system.  
17018025il 4il 41.0nitric oxide is synthesized by inos in microglia. inos protein expression was down regulated by il 4 in activated microglia when il 4 was given either before or after the triggering signal lipopolysaccharide.  
17018025il 4il 41.0more strikingly we found that il 4 increased motoneuron survival to a greater extent when added to mn + mc cocultures after lipopolysaccharide than when added prior to lipopolysaccharide.  
17018025il 4il 41.0in an effort to investigate the cause of this increase we examined the levels of il 4 mrna.  
17018025il 4il 41.0thus the greater expression of il 4r with the subsequent greater efficacy of the available il 4 could provide one potential explanation of the increased suppressive effects of il 4 on inos expression in activated microglia.  
17018025il 4il 41.0two studies have reported the inhibitory effects of il 4 on inos in lipopolysaccharide stimulated astrocytes and mixed glial cultures brodie et al 1998 ; kitamura et al 2000 although in their studies the cells were all treated with il 4 first and then stim 
17018025il 4il 41.0 on inos in lipopolysaccharide stimulated astrocytes and mixed glial cultures brodie et al 1998 ; kitamura et al 2000 although in their studies the cells were all treated with il 4 first and then stimulated cell with other triggering signals.  
17018025il 4il 41.0our present findings that il 4 also inhibits production in lipopolysaccharide activated microglia and that neuroprotection of il 4 was reversed by exogenous illustrate another potential neuroprotective aspect of this particular anti inflammatory cytokine.  
17018025il 4il 41.0 1995 reported that il 4 suppressed production in human microglia activated by tnf a or interferon ifn g.  
17018025il 4il 41.0it has been shown that il 4 reduces formation in macrophages via down regulation of gp9l phox at the mrna level zhou et al 1995 .  
17018025il 4il 41.0the ability of il 4 to suppress the production of both nitric oxide and suggests that il 4 can decrease the formation of peroxynitrite.  
17018025il 4il 41.0it has also been documented that neuroprotection of il 4 was attributed to down regulation of tnf a butovsky et al 2005 .  
17018025il 4il 41.0in accordance with this we did find lipopolysaccharide dramatically enhanced tnf a produced by microglia zhao et al 2004 and il 4 significantly decreased tnf a levels in mn + mc + lipopolysaccharide cocultures data not shown .  
17018025il 4il 41.0therefore down regulation of tnf a is one of mechanisms by which il 4 inhibited nitric oxide and production and protected motoneurons from microglia mediated toxicity.  
17018025il 4il 41.0another finding in the current study is that il 4 increased free igf 1 the active form of this neuroprotective factor in untreated microglia cultures and that lipopolysaccharide decreased free igf 1.  
17018025il 4il 41.0at first we hypothesized that the induction of free igf 1 in microglia might be another aspect of il 4 neuroprotection; however our subsequent results suggested it might not be.  
17018025il 4il 41.0il 4 increased motoneuron survival in both lipopolysaccharide treated mn + mc cocultures; however il 4 did not increase free igf 1 levels in the same cocultures.  
17018025il 4il 41.0in addition we saw no increase in igf 1 mrna in these lipopolysaccharide activated cultures although it has been reported that il 4 up regulated igf 1 mrna in both untreated and lipopolysaccharide activated microglia butovsky et al 2005 .  
17018025il 4il 41.0additionally even though free igf 1 was up regulated by il 4 in untreated microglia cocultured with motoneurons il 4 did not increase motoneuron survival under the same conditions.  
17018025il 4il 41.0therefore these results suggest that igf 1 may not be the primary mechanism of il 4 neuroprotection.  
17018025il 4il 41.0gh we cannot discount the possibility that there may have been an immediate local increase in igf 1 that was quickly sequestered by binding proteins it is likely that the free igf 1 levels induced by il 4 either before or after lipopolysaccharide in our system were not sufficient to elicit the neuroprotective effects.  
17018025il 4il 41.0several studies have demonstrated the beneficial effects of il 4 in the cns.  
17018025il 4il 41.0 1993 reported that il 4 blocked microglia mediated cerebral neuron injury.  
17018025il 4il 41.0it has also been reported that il 4 increased neuronal survival in hippocampal mixed cultures araujo and cotman 1993 .  
17018025il 4il 41.0il 4 delivered by transfected cells inhibited the progression and the severity of experimental autoimmune encephalomyelitis shaw et al 1997 ; furlan et al 2001 .  
17018025il 4il 41.0furthermore gene transfer of il 4 to the retina enhanced the survival of axotomized retinal ganglion cells koeberle et al 2004 .  
17018025il 4il 41.0while these studies demonstrate that il 4 can be neuroprotective few studies have examined the mechanisms of neuroprotection.  
17018025il 4il 41.0our present study provides evidence that il 4 protects motoneurons from injury partly by decreasing free radicals released from microglia and may not involve free igf 1.  
17018025il 4il 41.0whereas one paper reported that il 4 did not significantly suppress nitric oxide production from microglia when given 24 h after the triggering signals ifn g and lipopolysaccharide chao et al 1993 we found that il 4 was more neuroprotec 
17018025il 4il 41.0 did not significantly suppress nitric oxide production from microglia when given 24 h after the triggering signals ifn g and lipopolysaccharide chao et al 1993 we found that il 4 was more neuroprotective when added 2 h after lipopolysaccharide than before lipopolysaccharide.  
17018025il 4il 41.0besides il 4 il 10 and transforming growth factor beta tgf b are two other major anti inflammatory cytokines.  
17018025il 4il 41.0we had detected the effects of il 10 and tgf b in our mn + mc coculture system as well as il 4.  
17018025il 4il 41.0we found that il 4 had stronger protective effects on motoneurons than il 10.  
17018025il 4il 41.0like il 4 il 10 inhibited inos expression and nitric oxide production from microglia data not shown .  
17018025il 4il 41.0one potential source of the neuroprotective signal il 4 is th2 lymphocytes.  
17018025il 4il 41.0our present data suggest that il 4 may be one of the significant signals in t cell mediated neuroprotection.  
17018025il 4il 41.0accordingly immunological strategies to increase the presence of th2 lymphocytes and the release of il 4 would be a promising direction for treatment of neurodegenerative disorders.  
17018025il 4il 41.0in vivo studies will clearly be required to determine whether il 4 achieves neuroprotection by mitigating the neurotoxic effects of microglia.  
17018025interleukin 4interleukin 41.0anti inflammatory agents|inflammation mediators|lipopolysaccharides|neuroprotective agents|receptors interleukin 4|nitric oxide|superoxides|interleukin 4|insulin like growth factor i|  
17569578il 4il 41.0ion of this finding was further supported by a study of diab et al. showing that the endogenous ppar_amp_#x3b3; ligand 15d pgj 2 inhibited t cell proliferation and suppressed ifn_amp_#x3b3; il 10 and il 4 generation by activated lymphocytes [53] .  
17569578il 4il 41.0the authors showed that gemfibrozil and ciprofibrate induced il 4 production in murine and human lymphocytes while ifn_amp_#x3b3; production was decreased.  
18040778interleukin 4interleukin 41.0 2006 have advanced the concept of _amp_#8220;protective autoimmunity_amp_#8221; by demonstrating that whereas microglia activated by endotoxin block neurogenesis microglia activated by interleukin 4 or interferon g associated with cd4 lymphocyte infiltration induces neurogenesis.  
18464925il 4il 41.0in line with the beneficial effect of ppar _amp_#x003b3; agonists in experimental models of inflammatory diseases ppar _amp_#x003b3; has also been involved in anti inflammatory functions of il 4 a th2 type cytokine which plays an important role in controlling th1 cell responses and resolution of inflammation.  
18464925il 4il 41.0paintlia et al. [ 65 ] demonstrated that the inhibition of inos expression and the increase of survival of differentiating ops induced by il 4 in inflammatory cytokine stimulated mixed cultures are mediated by ppar _amp_#x003b3; activation.  
18464925il 4il 41.0in support of their conclusions the authors describe a coordinate increase in the expression of both ppar _amp_#x003b3; and its natural ligand producing enzyme 12/15 lipoxygenase 12/15 lox in il 4 treated glial cells and show that il 4 induced ppar _amp_#x003b3; activation antagonizes nf _amp_#x003ba; b transactivation in inflammatory cytokine stimulated astrocytes.  
18464925il 4il 41.0 treated glial cells and show that il 4 induced ppar _amp_#x003b3; activation antagonizes nf _amp_#x003ba; b transactivation in inflammatory cytokine stimulated astrocytes.  
18464925il 4il 41.0a similar upregulation of ppar _amp_#x003b3; by il 4 was demonstrated in cultured microglial cells [ 66 ].  
18464925il 4il 41.0to link between il 4 and ppar _amp_#x003b3; is completed by the observation that the anti inflammatory activity of the tzd troglitazone was mediated by its ability to increase il 4 expression in glial cultures [ 67 ].