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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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The synergistic interactions between TNF-α and AVP in the choroid plexus epithelium as assessed by the level of activation of JNK and its target transcription factors c-Jun and ATF2.The activation of the JNK signaling cascade in the Z310 cell line was assessed after 1-h incubation with either TNF-α (5 ng/ml) or a combination of TNF-α (5 ng/ml) and AVP (1 nM). In non-radioactive JNK activity assays, 200 ng of recombinant (rec) human c-Jun protein was used as a substrate for JNK. The extent of activation of c-Jun and ATF2 was assessed by Western blotting (30 µg of total protein per lane was loaded). The representative immunoblots are shown based on three independent experiments. 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.
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pone-0079328-g005: The synergistic interactions between TNF-α and AVP in the choroid plexus epithelium as assessed by the level of activation of JNK and its target transcription factors c-Jun and ATF2.The activation of the JNK signaling cascade in the Z310 cell line was assessed after 1-h incubation with either TNF-α (5 ng/ml) or a combination of TNF-α (5 ng/ml) and AVP (1 nM). In non-radioactive JNK activity assays, 200 ng of recombinant (rec) human c-Jun protein was used as a substrate for JNK. The extent of activation of c-Jun and ATF2 was assessed by Western blotting (30 µg of total protein per lane was loaded). The representative immunoblots are shown based on three independent experiments. 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.

Mentions: To confirm the results obtained with the pharmacological inhibition of JNK, we assessed changes in activation of JNK and its target transcription factors c-Jun and ATF2 in response to TNF-α or a combination of TNF-α and AVP using the JNK activity assays and Western blotting (Fig. 5). When added to the culture media at a concentration of 10–9 M, AVP by itself had no effect on JNK activity. However, it significantly augmented the TNF-α–dependent activation of this kinase. Similarly, AVP significantly increased the activation of c-Jun and ATF2 occurring in response to TNF-α, while on its own it had no effect on the level of phosphorylation of these transcription factors.


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)

The synergistic interactions between TNF-α and AVP in the choroid plexus epithelium as assessed by the level of activation of JNK and its target transcription factors c-Jun and ATF2.The activation of the JNK signaling cascade in the Z310 cell line was assessed after 1-h incubation with either TNF-α (5 ng/ml) or a combination of TNF-α (5 ng/ml) and AVP (1 nM). In non-radioactive JNK activity assays, 200 ng of recombinant (rec) human c-Jun protein was used as a substrate for JNK. The extent of activation of c-Jun and ATF2 was assessed by Western blotting (30 µg of total protein per lane was loaded). The representative immunoblots are shown based on three independent experiments. 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.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0079328-g005: The synergistic interactions between TNF-α and AVP in the choroid plexus epithelium as assessed by the level of activation of JNK and its target transcription factors c-Jun and ATF2.The activation of the JNK signaling cascade in the Z310 cell line was assessed after 1-h incubation with either TNF-α (5 ng/ml) or a combination of TNF-α (5 ng/ml) and AVP (1 nM). In non-radioactive JNK activity assays, 200 ng of recombinant (rec) human c-Jun protein was used as a substrate for JNK. The extent of activation of c-Jun and ATF2 was assessed by Western blotting (30 µg of total protein per lane was loaded). The representative immunoblots are shown based on three independent experiments. 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.
Mentions: To confirm the results obtained with the pharmacological inhibition of JNK, we assessed changes in activation of JNK and its target transcription factors c-Jun and ATF2 in response to TNF-α or a combination of TNF-α and AVP using the JNK activity assays and Western blotting (Fig. 5). When added to the culture media at a concentration of 10–9 M, AVP by itself had no effect on JNK activity. However, it significantly augmented the TNF-α–dependent activation of this kinase. Similarly, AVP significantly increased the activation of c-Jun and ATF2 occurring in response to TNF-α, while on its own it had no effect on the level of phosphorylation of these transcription factors.

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