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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 (A), and IL-1β and AVP (B) in the choroid plexus epithelium as assessed by real-time RT-PCR.Changes in production of CXCL1 in the choroid plexus epithelial cell line Z310 were assessed after 1-h incubation with either the cytokine (TNF-α or IL-1β) alone or a combination of the cytokine (TNF-α or IL-1β) and AVP. The exposure of Z310 cells to AVP alone at a concentration ranging between 0.1 nM and 1 µM resulted in only small increases in CXCL1 synthesis (a maximum increase observed was 6-fold relative to control with AVP at 100 nM). *p<0.05, **p<0.01 for treatment versus control. †p<0.05, ††p<0.01 for TNF-α + AVP versus TNF-α alone or for IL-1β + AVP versus IL-1β alone (n = 3–4 per group).
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pone-0079328-g002: The synergistic interactions between TNF-α and AVP (A), and IL-1β and AVP (B) in the choroid plexus epithelium as assessed by real-time RT-PCR.Changes in production of CXCL1 in the choroid plexus epithelial cell line Z310 were assessed after 1-h incubation with either the cytokine (TNF-α or IL-1β) alone or a combination of the cytokine (TNF-α or IL-1β) and AVP. The exposure of Z310 cells to AVP alone at a concentration ranging between 0.1 nM and 1 µM resulted in only small increases in CXCL1 synthesis (a maximum increase observed was 6-fold relative to control with AVP at 100 nM). *p<0.05, **p<0.01 for treatment versus control. †p<0.05, ††p<0.01 for TNF-α + AVP versus TNF-α alone or for IL-1β + AVP versus IL-1β alone (n = 3–4 per group).

Mentions: We next investigated the ability of AVP to stimulate the chemokine production in the CP epithelial cell cultures. For these experiments, the CP epithelial cell line Z310 was employed. Using RT-PCR, we confirmed the presence of the AVPR1A in the Z310 cells. The AVPR1B or AVPR2 was not expressed in these cells. The effect of AVP on CXCL1 synthesis was examined, with the AVP concentration ranging between 10–10 and 10–6 M. After 1-h incubation, the maximum effect was observed at a peptide concentration of 10–7 M, but AVP produced only a moderate (6-fold) increase in CXCL1 mRNA. Therefore, we tested the hypothesis that AVP acts synergistically with proinflammatory cytokines to amplify the cytokine-dependent production of chemokines. A significantly larger increase in CXCL1 mRNA was observed after the Z310 cells were exposed to a combination of TNF-α and AVP compared to the increase in CXCL1 synthesis seen in these cells after exposure to TNF-α alone (Fig. 2A). Similarly, AVP augmented the IL-1β–dependent increase in expression of CXCL1, but the levels of CXCL1 mRNA were substantially higher than those found in response to TNF-α or a combination of TNF-α and AVP (Fig. 2B).


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 (A), and IL-1β and AVP (B) in the choroid plexus epithelium as assessed by real-time RT-PCR.Changes in production of CXCL1 in the choroid plexus epithelial cell line Z310 were assessed after 1-h incubation with either the cytokine (TNF-α or IL-1β) alone or a combination of the cytokine (TNF-α or IL-1β) and AVP. The exposure of Z310 cells to AVP alone at a concentration ranging between 0.1 nM and 1 µM resulted in only small increases in CXCL1 synthesis (a maximum increase observed was 6-fold relative to control with AVP at 100 nM). *p<0.05, **p<0.01 for treatment versus control. †p<0.05, ††p<0.01 for TNF-α + AVP versus TNF-α alone or for IL-1β + AVP versus IL-1β alone (n = 3–4 per group).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0079328-g002: The synergistic interactions between TNF-α and AVP (A), and IL-1β and AVP (B) in the choroid plexus epithelium as assessed by real-time RT-PCR.Changes in production of CXCL1 in the choroid plexus epithelial cell line Z310 were assessed after 1-h incubation with either the cytokine (TNF-α or IL-1β) alone or a combination of the cytokine (TNF-α or IL-1β) and AVP. The exposure of Z310 cells to AVP alone at a concentration ranging between 0.1 nM and 1 µM resulted in only small increases in CXCL1 synthesis (a maximum increase observed was 6-fold relative to control with AVP at 100 nM). *p<0.05, **p<0.01 for treatment versus control. †p<0.05, ††p<0.01 for TNF-α + AVP versus TNF-α alone or for IL-1β + AVP versus IL-1β alone (n = 3–4 per group).
Mentions: We next investigated the ability of AVP to stimulate the chemokine production in the CP epithelial cell cultures. For these experiments, the CP epithelial cell line Z310 was employed. Using RT-PCR, we confirmed the presence of the AVPR1A in the Z310 cells. The AVPR1B or AVPR2 was not expressed in these cells. The effect of AVP on CXCL1 synthesis was examined, with the AVP concentration ranging between 10–10 and 10–6 M. After 1-h incubation, the maximum effect was observed at a peptide concentration of 10–7 M, but AVP produced only a moderate (6-fold) increase in CXCL1 mRNA. Therefore, we tested the hypothesis that AVP acts synergistically with proinflammatory cytokines to amplify the cytokine-dependent production of chemokines. A significantly larger increase in CXCL1 mRNA was observed after the Z310 cells were exposed to a combination of TNF-α and AVP compared to the increase in CXCL1 synthesis seen in these cells after exposure to TNF-α alone (Fig. 2A). Similarly, AVP augmented the IL-1β–dependent increase in expression of CXCL1, but the levels of CXCL1 mRNA were substantially higher than those found in response to TNF-α or a combination of TNF-α and AVP (Fig. 2B).

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