Contributions
Abstract: EP1778
Type: ePoster
Abstract Category: Therapy - disease modifying - 31 Treatment of progressive MS
Laquinimod is an orally-delivered immunomodulator which includes actions on the innate immune system and is in clinical trials for primary progressive multiple sclerosis. Laquinimod crosses the blood-brain barrier and enters the CNS, and recent studies suggest that in addition to peripheral actions, it may also exert its effects via direct modulation of reactive astrogliosis, which increasing evidence implicates as a key regulatory mechanism controlling CNS inflammation. Here, we report that laquinimod strongly impacts proinflammatory gene expression in a primary human model of reactive astrogliosis in vitro. Interleukin-1beta (IL-1β) is implicated in lesion pathogenesis in MS, and is a strong inducer of astroglial reactivity in human cultures. We examined the impact of laquinimod on human astrocytic responses to IL-1β treatment. Notably, we found that IL-1β 10ng/ml induced a pro-inflammatory transcriptional pattern in primary human astrocytes, which encompassed induction of inflammatory cytokines, reactive nitrogen species, chemokines, adhesion molecules, matrix metalloproteinases, and inducers of endothelial plasticity and blood-brain barrier permeability, as shown by microarray, QPCR and multiplex ELISA. Importantly, at therapeutic concentrations, laquinimod dose-dependently inhibited IL-1β induction of cytokines including TNFα, IL-6, IFNα, IL-12 and IL-23, inducible nitric oxide synthase, and the matrix metalloproteases MMP7 and MMP10. Suggesting immunomodulation rather than suppression, laquinimod differentially regulated IL-1β-induced expression of CXC and CC chemokines, inhibiting induction of CXCL1,2,5,6,8 and 10, and CCL8, while potentiating CCL5. IL-1β signals via the transcription factor NF-κB, and suggesting mechanism, laquinimod treatment delayed IL-1β-induced IκBα degradation and NF-κB p65 nuclear translocation. Moreover, compatible with a recent in vivo study, our data suggest that laquinimod acts as a ligand for the aryl hydrocarbon receptor (AhR), a potent immunoregulator that restricts NFκB activation via direct interaction with its p65 subunit. Collectively, these data reveal laquinimod as a regulator of the proinflammatory phenotype in a human model of reactive astrogliosis, and suggest that it may act in part via AhR-mediated inhibition of NF-κB activation.
Disclosure: This research project has been funded by Teva Pharmaceuticals and Neta Zach is an employee from Teva Pharmaceuticals.
Abstract: EP1778
Type: ePoster
Abstract Category: Therapy - disease modifying - 31 Treatment of progressive MS
Laquinimod is an orally-delivered immunomodulator which includes actions on the innate immune system and is in clinical trials for primary progressive multiple sclerosis. Laquinimod crosses the blood-brain barrier and enters the CNS, and recent studies suggest that in addition to peripheral actions, it may also exert its effects via direct modulation of reactive astrogliosis, which increasing evidence implicates as a key regulatory mechanism controlling CNS inflammation. Here, we report that laquinimod strongly impacts proinflammatory gene expression in a primary human model of reactive astrogliosis in vitro. Interleukin-1beta (IL-1β) is implicated in lesion pathogenesis in MS, and is a strong inducer of astroglial reactivity in human cultures. We examined the impact of laquinimod on human astrocytic responses to IL-1β treatment. Notably, we found that IL-1β 10ng/ml induced a pro-inflammatory transcriptional pattern in primary human astrocytes, which encompassed induction of inflammatory cytokines, reactive nitrogen species, chemokines, adhesion molecules, matrix metalloproteinases, and inducers of endothelial plasticity and blood-brain barrier permeability, as shown by microarray, QPCR and multiplex ELISA. Importantly, at therapeutic concentrations, laquinimod dose-dependently inhibited IL-1β induction of cytokines including TNFα, IL-6, IFNα, IL-12 and IL-23, inducible nitric oxide synthase, and the matrix metalloproteases MMP7 and MMP10. Suggesting immunomodulation rather than suppression, laquinimod differentially regulated IL-1β-induced expression of CXC and CC chemokines, inhibiting induction of CXCL1,2,5,6,8 and 10, and CCL8, while potentiating CCL5. IL-1β signals via the transcription factor NF-κB, and suggesting mechanism, laquinimod treatment delayed IL-1β-induced IκBα degradation and NF-κB p65 nuclear translocation. Moreover, compatible with a recent in vivo study, our data suggest that laquinimod acts as a ligand for the aryl hydrocarbon receptor (AhR), a potent immunoregulator that restricts NFκB activation via direct interaction with its p65 subunit. Collectively, these data reveal laquinimod as a regulator of the proinflammatory phenotype in a human model of reactive astrogliosis, and suggest that it may act in part via AhR-mediated inhibition of NF-κB activation.
Disclosure: This research project has been funded by Teva Pharmaceuticals and Neta Zach is an employee from Teva Pharmaceuticals.