Contributions
Abstract: P1869
Type: Poster
Abstract Category: Late breaking news
Introduction: The structurally related cytokines LIF and IL-6 have polar opposite effects on T lymphocyte lineage maturation, creating a pivotal LIF/IL-6 axis. Here LIF promotes tolerogenic Treg; IL-6 promotes inflammatory TH17. Since increased circulating levels of IL-6 correlate with decreased Treg in multiple sclerosis (MS), we ask - is there a LIF/IL-6 axis at the blood brain barrier (BBB) that may influence disease pathogenesis?
Hypothesis: LIF is a neuro-protective cytokine released by astrocytes and also entering the CNS across the BBB via a LIF-specific transporter, gp190. We now ask, is there an IL-6-specific transporter at the BBB that might impact the balance between LIF and IL-6 within the CNS?
Methods: In mice, acute kinetic studies used radiolabelled iodine 125I-IL-6 to track IL-6 following intravenous delivery into the jugular vein. Samples from the carotid artery were taken at 1, 2, 3, 4, 5, 6, 7.5, 9, 10, 12.5, and 15 minutes: at each time point the mouse was decapitated and the brain collected. Experimental groups were - GROUP A:125I-IL-6 only; GROUP B: 125I-IL-6 plus excess unlabeled IL-6; GROUP C: 125I-IL-6 plus excess unlabeled LIF. Technetium (99mTc) labeled albumin was premixed with the 125I-IL-6 prior to use to control for background.
Results:
· GROUP A: (125I-IL-6), there was a linear time-dependent increase of radioactivity in the brain reaching some 15-fold by 15 minutes.
· GROUP B: (125I-IL-6/excess cold-IL-6) there was very little increase in radioactivity in the brain (2-fold at 15 min), implying excess of unlabeled IL-6 specifically competed out the BBB transport of 125I-IL-6.
· GROUP C: (125I-IL-6/excess cold-LIF) 125I-IL-6 entry into the brain compartment was the same as that in GROUP A. Thus, LIF did not compete for the IL-6 transporter.
Conclusion: IL-6 crosses the BBB via an IL-6-specific transporter without being inhibited by LIF. Since gp190, the LIF-specific receptor, is required for LIF to cross the BBB, then two separate transporter systems impact the homeostatic balance between LIF and IL-6 within the CNS.
Discussion: Circulating IL-6 may increase during inflammatory immunity or EBV activity and chronically increased IL-6 levels may tip the balance of LIF versus IL-6 in favour of IL-6. To reset homeostasis, therapeutic use of exogenous LIF in PLGA nano-formulation (LIFNano), is warranted, where LIFNano is proven to oppose TH17 immunity, promote myelin repair, and to be neuroprotective.
Disclosure: Su Metcalfe: Principle Investigator Innovate-UK Biomedical Catalyst Award Project Ref 510136: founder and CSO of LIFNano Therapeutics Ltd.
Gavin Giovannoni: Collaborator Innovate-UK Biomedical Catalyst Award 2017 Project Ref 510136. Nothing to disclose.
William A Banks: supported by the US Department of Veterans Affairs and a grant from the US National Institute on Aging (grant R01 AG046619). Nothing to disclose.W Pan nothing to disclose.
Abstract: P1869
Type: Poster
Abstract Category: Late breaking news
Introduction: The structurally related cytokines LIF and IL-6 have polar opposite effects on T lymphocyte lineage maturation, creating a pivotal LIF/IL-6 axis. Here LIF promotes tolerogenic Treg; IL-6 promotes inflammatory TH17. Since increased circulating levels of IL-6 correlate with decreased Treg in multiple sclerosis (MS), we ask - is there a LIF/IL-6 axis at the blood brain barrier (BBB) that may influence disease pathogenesis?
Hypothesis: LIF is a neuro-protective cytokine released by astrocytes and also entering the CNS across the BBB via a LIF-specific transporter, gp190. We now ask, is there an IL-6-specific transporter at the BBB that might impact the balance between LIF and IL-6 within the CNS?
Methods: In mice, acute kinetic studies used radiolabelled iodine 125I-IL-6 to track IL-6 following intravenous delivery into the jugular vein. Samples from the carotid artery were taken at 1, 2, 3, 4, 5, 6, 7.5, 9, 10, 12.5, and 15 minutes: at each time point the mouse was decapitated and the brain collected. Experimental groups were - GROUP A:125I-IL-6 only; GROUP B: 125I-IL-6 plus excess unlabeled IL-6; GROUP C: 125I-IL-6 plus excess unlabeled LIF. Technetium (99mTc) labeled albumin was premixed with the 125I-IL-6 prior to use to control for background.
Results:
· GROUP A: (125I-IL-6), there was a linear time-dependent increase of radioactivity in the brain reaching some 15-fold by 15 minutes.
· GROUP B: (125I-IL-6/excess cold-IL-6) there was very little increase in radioactivity in the brain (2-fold at 15 min), implying excess of unlabeled IL-6 specifically competed out the BBB transport of 125I-IL-6.
· GROUP C: (125I-IL-6/excess cold-LIF) 125I-IL-6 entry into the brain compartment was the same as that in GROUP A. Thus, LIF did not compete for the IL-6 transporter.
Conclusion: IL-6 crosses the BBB via an IL-6-specific transporter without being inhibited by LIF. Since gp190, the LIF-specific receptor, is required for LIF to cross the BBB, then two separate transporter systems impact the homeostatic balance between LIF and IL-6 within the CNS.
Discussion: Circulating IL-6 may increase during inflammatory immunity or EBV activity and chronically increased IL-6 levels may tip the balance of LIF versus IL-6 in favour of IL-6. To reset homeostasis, therapeutic use of exogenous LIF in PLGA nano-formulation (LIFNano), is warranted, where LIFNano is proven to oppose TH17 immunity, promote myelin repair, and to be neuroprotective.
Disclosure: Su Metcalfe: Principle Investigator Innovate-UK Biomedical Catalyst Award Project Ref 510136: founder and CSO of LIFNano Therapeutics Ltd.
Gavin Giovannoni: Collaborator Innovate-UK Biomedical Catalyst Award 2017 Project Ref 510136. Nothing to disclose.
William A Banks: supported by the US Department of Veterans Affairs and a grant from the US National Institute on Aging (grant R01 AG046619). Nothing to disclose.W Pan nothing to disclose.