Ethanol-Induced Activation of Myosin Light Chain Kinase Leads to Dysfunction of Tight Junctions and Blood-Brain Barrier Compromise

Haorah, James; Heilman, David; Knipe, Bryan; Chrastil, Jesse; Leibhart, Jessica; Ghorpade, Anuja; Miller, Donald W.; Persidsky, Yuri

doi:10.1097/01.alc.0000166944.79914.0a

Cited by 154 publications

(165 citation statements)

References 64 publications

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“…Our results suggest that PKCε's role in metastasis may be related to its ability to impair the barrier function (and cell adhesion) through phosphorylation of TJ proteins such as claudin-4. These findings are consistent with a number of studies that have previously shown that phosphorylation of various claudin proteins can decrease TJ integrity [32,35,[51][52][53][54], although phosphorylation of claudin-1 has also been shown to promote barrier function [29,31]. However, it is important to note that TJ disruption likely occurs through multiple mechanisms.…”

Section: Discussionsupporting

confidence: 90%

Phosphorylation of claudin-4 by PKCε regulates tight junction barrier function in ovarian cancer cells

D’Souza

Indig

Morin

2007

Experimental Cell Research

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Claudin proteins belong to a large family of transmembrane proteins essential to the formation and maintenance of tight junctions (TJs). In ovarian cancer, TJ protein claudin-4 is frequently overexpressed and may have roles in survival and invasion, but the molecular mechanisms underlying its regulation are poorly understood. In this report, we show that claudin-4 can be phosphorylated by protein kinase C (PKC) at Thr189 and Ser194 in ovarian cancer cells and overexpression of a claudin-4 mutant protein mimicking the phosphorylated state results in the disruption of the barrier function. Furthermore, upon phorbol ester-mediated PKC activation of OVCA433 cells, TJ strength is decreased and claudin-4 localization is altered. Analyses using PKC inhibitors and siRNA suggest that PKCε, an isoform typically expressed in ovarian cancer cells, may be important in the TPAmediated claudin-4 phosphorylation and weakening of the TJs. Furthermore, immunofluorescence studies showed that claudin-4 and PKCε are co-localized at the TJs in these cells. The modulation of claudin-4 activity by PKCε may not only provide a mechanism for disrupting TJ function in ovarian cancer, but may also be important in the regulation of TJ function in normal epithelial cells.

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Section: Discussionsupporting

confidence: 90%

Phosphorylation of claudin-4 by PKCε regulates tight junction barrier function in ovarian cancer cells

D’Souza

Indig

Morin

2007

Experimental Cell Research

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“…BBB showed edema and abnormal mitochondria (Karwacka, 1980). Partial disruption of the BBB and increased nonspecific paracellular permeability are also consistent with the observation in vitro that alcohol treatment activates myosin light chain kinase, alters the distribution and function of the tight junction proteins occludin and claudin-5, and reduces transendothelial electrical resistance (Haorah et al, 2005a).…”

Section: Discussionsupporting

confidence: 85%

Increased Leptin Permeation across the Blood–Brain Barrier after Chronic Alcohol Ingestion

Pan

Barron

Hsuchou

et al. 2007

Neuropsychopharmacol

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Leptin, a polypeptide mainly produced in the periphery, crosses the blood-brain barrier (BBB) by receptor-mediated transport to exert multiple central nervous system actions including decreased food intake. The reciprocal interactions between leptin transport and alcohol drinking are not clear. In this study, we tested whether alcohol increases leptin entry into brain and, if this occurs, whether it is a consequence of a generalized increase in the permeability of the BBB. BBB permeability to albumin, the increased permeation of which indicates BBB disruption, as well as to leptin was measured after alcohol ingestion. CD1 and B6 mice ingested a 5% liquid alcohol diet or its isocaloric control for 2 weeks. Alcohol ingestion resulted in increased blood-alcohol levels, decreased blood-leptin concentrations, and increased permeation of radioactively labeled leptin across the BBB as shown by in situ perfusion. Although the increased influx of the vascular marker albumin into brain showed partial disruption of the BBB, the influx of 125 I-leptin still could be suppressed by excess unlabeled leptin, indicating persistence of its saturable transport system. When given a choice of either alcohol or control diet, even the alcohol-preferring B6 mice showed a significantly greater preference for the control liquid diet, and there was no evidence of BBB disruption or alterated leptin transport. Furthermore, acute alcohol intoxication induced by intraperitoneal injection of 20% alcohol did not result in BBB disruption or increased leptin permeation 4 h later. Thus, partial disruption of the BBB and increased permeation of leptin in both CD1 and B6 mice were only induced by chronic alcohol ingestion. The results showing increased leptin permeation across the BBB lead to the speculation that leptin may serve as a homeostatic feeding signal in these mice.

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“…Further studies will investigate this in more detail. MLC phosphorylation in endothelial cells induces transient cytoskeletal reorganization, cell retraction, and conformational changes in tight junction proteins that can conceal immunoreactive epitopes and inhibition of MLC kinase prevents hypoxia-induced opening of the BBB in vitro (Wysolmerski and Lagunoff, 1990;Haorah et al, 2005;Kuhlmann et al, 2007). This cascade could explain the severe but transient loss of immunoreactive claudin-5 in vehicle-treated mice and the hyper-acute MMP-9-independent phase of disruption in IL-1␤-challenged mice.…”

Section: Discussionmentioning

confidence: 99%

Systemic Inflammation Alters the Kinetics of Cerebrovascular Tight Junction Disruption after Experimental Stroke in Mice

McColl¹,

Rothwell²,

Allan³

2008

J. Neurosci.

286

262

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Systemic inflammatory events, such as infection, increase the risk of stroke and are associated with worse outcome, but the mediators of this clinically important effect are unknown. Our aim here was to elucidate mechanisms contributing to the detrimental effects of systemic inflammation on mild ischemic brain injury in mice. Systemic inflammation was induced in mice by peripheral interleukin-1␤ (IL-1␤) challenge and focal cerebral ischemia by transient middle cerebral artery occlusion (MCAo). Systemic inflammation caused an alteration in the kinetics of blood-brain barrier (BBB) disruption through conversion of a transient to a sustained disruption of the tight junction protein, claudin-5, and also markedly exacerbated disruption to the cerebrovascular basal lamina protein, collagen-IV. These alterations were associated with a systemic inflammation-induced increase in neurovascular gelatinolytic activity that was mediated by a fivefold increase in neutrophil-derived matrix metalloproteinase-9 (MMP-9) in the brains of IL-1␤-challenged mice after MCAo. Specific inhibition of MMP-9 abrogated the effects of systemic inflammation on the sustained but not the acute disruption of claudin-5, which was associated with phosphorylation of cerebrovascular myosin light chain. MMP-9 inhibition also attenuated the deleterious impact of systemic inflammation on brain damage, edema, neurological deficit, and incidence of hemorrhagic transformation. These data indicate that a transformation from transient to sustained BBB disruption caused by enhanced neutrophil-derived neurovascular MMP-9 activity is a critical mechanism underlying the exacerbation of ischemic brain injury by systemic inflammation. These mechanisms may contribute to the poor clinical outcome in stroke patients presenting with antecedent infection.

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Ethanol-Induced Activation of Myosin Light Chain Kinase Leads to Dysfunction of Tight Junctions and Blood-Brain Barrier Compromise

Cited by 154 publications

References 64 publications

Phosphorylation of claudin-4 by PKCε regulates tight junction barrier function in ovarian cancer cells

Phosphorylation of claudin-4 by PKCε regulates tight junction barrier function in ovarian cancer cells

Increased Leptin Permeation across the Blood–Brain Barrier after Chronic Alcohol Ingestion

Systemic Inflammation Alters the Kinetics of Cerebrovascular Tight Junction Disruption after Experimental Stroke in Mice

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