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Synergistic interactions between cytokines and AVP at the blood-CSF barrier result in increased chemokine production and augmented influx of leukocytes after brain injury.

Szmydynger-Chodobska J, Gandy JR, Varone A, Shan R, Chodobski A - PLoS ONE (2013)

Bottom Line: Arginine vasopressin was also found to play an important role in post-traumatic activation of c-Jun N-terminal kinase (JNK) in the CP.Under in vivo conditions, a selective JNK inhibitor decreased the post-traumatic production of neutrophil chemoattractants by the CP and reduced the influx of neutrophils across the BCSFB.These results provide evidence for the synergistic interactions between proinflammatory cytokines and AVP, a ligand for G protein-coupled receptors, and support a pathophysiological role of AVP in post-traumatic neuroinflammation.

View Article: PubMed Central - PubMed

Affiliation: The Neurotrauma and Brain Barriers Research Laboratory, Department of Emergency Medicine, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.

ABSTRACT
Several lines of evidence indicate that the blood-cerebrospinal fluid barrier (BCSFB), which primarily resides in the choroid plexus (CP), plays a significant pathophysiological role not only in neuroinflammatory diseases, such as multiple sclerosis, but also in traumatic brain injury (TBI). Here we investigated how arginine vasopressin (AVP) regulates function of the BCSFB in the context of post-traumatic neuroinflammation. It has previously been shown that AVP exacerbates various forms of brain injury, but the mechanisms underlying this AVP action are poorly understood. Type 1A AVP receptor is highly expressed on the CP epithelium and the CP synthesizes AVP. Using the controlled cortical impact model of TBI, we demonstrated decreased post-traumatic production of proinflammatory mediators by the CP and reduced influx of inflammatory cells across the BCSFB in AVP-deficient Brattleboro rats when compared with Long-Evans rats, a parental strain for Brattleboro rats. Arginine vasopressin was also found to play an important role in post-traumatic activation of c-Jun N-terminal kinase (JNK) in the CP. In the CP epithelial cell cultures, AVP augmented the tumor necrosis factor-α- and interleukin-1β-dependent increase in synthesis of proinflammatory mediators, including neutrophil chemoattractants, an action largely dependent on the JNK signaling pathway. Under in vivo conditions, a selective JNK inhibitor decreased the post-traumatic production of neutrophil chemoattractants by the CP and reduced the influx of neutrophils across the BCSFB. These results provide evidence for the synergistic interactions between proinflammatory cytokines and AVP, a ligand for G protein-coupled receptors, and support a pathophysiological role of AVP in post-traumatic neuroinflammation.

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Post-traumatic activation of JNK in the lateral ventricle choroid plexus (CP) as assessed by Western blotting and JNK activity assays at 6 h after injury.A comparison of AVP-deficient Brattleboro rats (Avpdi/di) with their parental Long-Evans strain (WT). The activity of JNK was assessed in both the ipsilateral (Ipsi CP/I) and contralateral (Contr CP/C) CPs. For Western blotting, 40 µg of total protein per lane was loaded. In non-radioactive JNK activity assays, 200 ng of recombinant (rec) human c-Jun protein was used as a substrate for JNK. Similar results were obtained in an independent experiment involving separate groups of animals. The ratios of optical density of bands for phosphorylated proteins over the optical density of bands for the total (phosphorylated and non-phosphorylated) proteins are shown (n = 4 per group).
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pone-0079328-g006: Post-traumatic activation of JNK in the lateral ventricle choroid plexus (CP) as assessed by Western blotting and JNK activity assays at 6 h after injury.A comparison of AVP-deficient Brattleboro rats (Avpdi/di) with their parental Long-Evans strain (WT). The activity of JNK was assessed in both the ipsilateral (Ipsi CP/I) and contralateral (Contr CP/C) CPs. For Western blotting, 40 µg of total protein per lane was loaded. In non-radioactive JNK activity assays, 200 ng of recombinant (rec) human c-Jun protein was used as a substrate for JNK. Similar results were obtained in an independent experiment involving separate groups of animals. The ratios of optical density of bands for phosphorylated proteins over the optical density of bands for the total (phosphorylated and non-phosphorylated) proteins are shown (n = 4 per group).

Mentions: In wild-type rats, TBI resulted in a rapid (within 6 h post-injury) activation of JNK in the ipsilateral CP, which was determined by Western blotting with phospho-specific anti-JNK antibodies and the JNK activity assays (Fig. 6). The extent of post-traumatic activation of JNK in the ipsilateral CP was considerably attenuated in Avpdi/di rats, suggesting the important role of this neuropeptide in the activation of this signaling pathway after injury.


Synergistic interactions between cytokines and AVP at the blood-CSF barrier result in increased chemokine production and augmented influx of leukocytes after brain injury.

Szmydynger-Chodobska J, Gandy JR, Varone A, Shan R, Chodobski A - PLoS ONE (2013)

Post-traumatic activation of JNK in the lateral ventricle choroid plexus (CP) as assessed by Western blotting and JNK activity assays at 6 h after injury.A comparison of AVP-deficient Brattleboro rats (Avpdi/di) with their parental Long-Evans strain (WT). The activity of JNK was assessed in both the ipsilateral (Ipsi CP/I) and contralateral (Contr CP/C) CPs. For Western blotting, 40 µg of total protein per lane was loaded. In non-radioactive JNK activity assays, 200 ng of recombinant (rec) human c-Jun protein was used as a substrate for JNK. Similar results were obtained in an independent experiment involving separate groups of animals. The ratios of optical density of bands for phosphorylated proteins over the optical density of bands for the total (phosphorylated and non-phosphorylated) proteins are shown (n = 4 per group).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3815129&req=5

pone-0079328-g006: Post-traumatic activation of JNK in the lateral ventricle choroid plexus (CP) as assessed by Western blotting and JNK activity assays at 6 h after injury.A comparison of AVP-deficient Brattleboro rats (Avpdi/di) with their parental Long-Evans strain (WT). The activity of JNK was assessed in both the ipsilateral (Ipsi CP/I) and contralateral (Contr CP/C) CPs. For Western blotting, 40 µg of total protein per lane was loaded. In non-radioactive JNK activity assays, 200 ng of recombinant (rec) human c-Jun protein was used as a substrate for JNK. Similar results were obtained in an independent experiment involving separate groups of animals. The ratios of optical density of bands for phosphorylated proteins over the optical density of bands for the total (phosphorylated and non-phosphorylated) proteins are shown (n = 4 per group).
Mentions: In wild-type rats, TBI resulted in a rapid (within 6 h post-injury) activation of JNK in the ipsilateral CP, which was determined by Western blotting with phospho-specific anti-JNK antibodies and the JNK activity assays (Fig. 6). The extent of post-traumatic activation of JNK in the ipsilateral CP was considerably attenuated in Avpdi/di rats, suggesting the important role of this neuropeptide in the activation of this signaling pathway after injury.

Bottom Line: Arginine vasopressin was also found to play an important role in post-traumatic activation of c-Jun N-terminal kinase (JNK) in the CP.Under in vivo conditions, a selective JNK inhibitor decreased the post-traumatic production of neutrophil chemoattractants by the CP and reduced the influx of neutrophils across the BCSFB.These results provide evidence for the synergistic interactions between proinflammatory cytokines and AVP, a ligand for G protein-coupled receptors, and support a pathophysiological role of AVP in post-traumatic neuroinflammation.

View Article: PubMed Central - PubMed

Affiliation: The Neurotrauma and Brain Barriers Research Laboratory, Department of Emergency Medicine, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.

ABSTRACT
Several lines of evidence indicate that the blood-cerebrospinal fluid barrier (BCSFB), which primarily resides in the choroid plexus (CP), plays a significant pathophysiological role not only in neuroinflammatory diseases, such as multiple sclerosis, but also in traumatic brain injury (TBI). Here we investigated how arginine vasopressin (AVP) regulates function of the BCSFB in the context of post-traumatic neuroinflammation. It has previously been shown that AVP exacerbates various forms of brain injury, but the mechanisms underlying this AVP action are poorly understood. Type 1A AVP receptor is highly expressed on the CP epithelium and the CP synthesizes AVP. Using the controlled cortical impact model of TBI, we demonstrated decreased post-traumatic production of proinflammatory mediators by the CP and reduced influx of inflammatory cells across the BCSFB in AVP-deficient Brattleboro rats when compared with Long-Evans rats, a parental strain for Brattleboro rats. Arginine vasopressin was also found to play an important role in post-traumatic activation of c-Jun N-terminal kinase (JNK) in the CP. In the CP epithelial cell cultures, AVP augmented the tumor necrosis factor-α- and interleukin-1β-dependent increase in synthesis of proinflammatory mediators, including neutrophil chemoattractants, an action largely dependent on the JNK signaling pathway. Under in vivo conditions, a selective JNK inhibitor decreased the post-traumatic production of neutrophil chemoattractants by the CP and reduced the influx of neutrophils across the BCSFB. These results provide evidence for the synergistic interactions between proinflammatory cytokines and AVP, a ligand for G protein-coupled receptors, and support a pathophysiological role of AVP in post-traumatic neuroinflammation.

Show MeSH
Related in: MedlinePlus