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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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Signal transduction pathways involved in the synergistic interactions between TNF-α and AVP.The experiments were conducted on the choroid plexus epithelial cell line Z310 and changes in production of CXCL1 were assessed by real-time RT-PCR. To inhibit JNK (SP600125; 10 µM) or p38 (SB203580; 1 µM) activity, or to interfere with ERK (MEK1 inhibitor PD-98059; 10 µM) or NF-κB (SN50; 100 µg/ml) signaling, the Z3110 cells were pre-incubated for 1 h with respective inhibitors. These inhibitors were also added to the culture media when the cells were exposed to TNF-α (5 ng/ml) or a combination of TNF-α (5 ng/ml) and AVP (1 nM) for an additional hour. Note that the selective JNK inhibitor SP600125 completely abolished the induction of CXCL1 synthesis observed in response to TNF-α alone or to a combination of TNF-α and AVP. A selective MEK1 inhibitor PD-98059 partially (by >50%) inhibited CXCL1 synthesis, whereas p38 inhibitor SB203580 had no effect. In comparison, the inhibition of NF-κB signaling resulted in the amplification of chemokine synthesis. *p<0.05, **p<0.01 for treatment versus control. †p<0.05, ††p<0.01 for the incubation with inhibitor versus the incubation without inhibitor (n = 3 per group).
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pone-0079328-g004: Signal transduction pathways involved in the synergistic interactions between TNF-α and AVP.The experiments were conducted on the choroid plexus epithelial cell line Z310 and changes in production of CXCL1 were assessed by real-time RT-PCR. To inhibit JNK (SP600125; 10 µM) or p38 (SB203580; 1 µM) activity, or to interfere with ERK (MEK1 inhibitor PD-98059; 10 µM) or NF-κB (SN50; 100 µg/ml) signaling, the Z3110 cells were pre-incubated for 1 h with respective inhibitors. These inhibitors were also added to the culture media when the cells were exposed to TNF-α (5 ng/ml) or a combination of TNF-α (5 ng/ml) and AVP (1 nM) for an additional hour. Note that the selective JNK inhibitor SP600125 completely abolished the induction of CXCL1 synthesis observed in response to TNF-α alone or to a combination of TNF-α and AVP. A selective MEK1 inhibitor PD-98059 partially (by >50%) inhibited CXCL1 synthesis, whereas p38 inhibitor SB203580 had no effect. In comparison, the inhibition of NF-κB signaling resulted in the amplification of chemokine synthesis. *p<0.05, **p<0.01 for treatment versus control. †p<0.05, ††p<0.01 for the incubation with inhibitor versus the incubation without inhibitor (n = 3 per group).

Mentions: To identify the signal transduction pathways mediating AVP action on the choroidal epithelium, we used selective inhibitors of JNK, MEK1, and p38. In the cultures of the Z310 cells, the inhibition of JNK completely abolished an increase in CXCL1 expression observed in response to either TNF-α or a combination of TNF-α and AVP (Fig. 4). The inhibition of ERK signaling only partially reduced the production of CXCL1, whereas the inhibition of p38 had no effect on chemokine synthesis. Interestingly, the inhibition of NF-κB signaling actually increased the synthesis of CXCL1 by the choroidal epithelium.


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)

Signal transduction pathways involved in the synergistic interactions between TNF-α and AVP.The experiments were conducted on the choroid plexus epithelial cell line Z310 and changes in production of CXCL1 were assessed by real-time RT-PCR. To inhibit JNK (SP600125; 10 µM) or p38 (SB203580; 1 µM) activity, or to interfere with ERK (MEK1 inhibitor PD-98059; 10 µM) or NF-κB (SN50; 100 µg/ml) signaling, the Z3110 cells were pre-incubated for 1 h with respective inhibitors. These inhibitors were also added to the culture media when the cells were exposed to TNF-α (5 ng/ml) or a combination of TNF-α (5 ng/ml) and AVP (1 nM) for an additional hour. Note that the selective JNK inhibitor SP600125 completely abolished the induction of CXCL1 synthesis observed in response to TNF-α alone or to a combination of TNF-α and AVP. A selective MEK1 inhibitor PD-98059 partially (by >50%) inhibited CXCL1 synthesis, whereas p38 inhibitor SB203580 had no effect. In comparison, the inhibition of NF-κB signaling resulted in the amplification of chemokine synthesis. *p<0.05, **p<0.01 for treatment versus control. †p<0.05, ††p<0.01 for the incubation with inhibitor versus the incubation without inhibitor (n = 3 per group).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0079328-g004: Signal transduction pathways involved in the synergistic interactions between TNF-α and AVP.The experiments were conducted on the choroid plexus epithelial cell line Z310 and changes in production of CXCL1 were assessed by real-time RT-PCR. To inhibit JNK (SP600125; 10 µM) or p38 (SB203580; 1 µM) activity, or to interfere with ERK (MEK1 inhibitor PD-98059; 10 µM) or NF-κB (SN50; 100 µg/ml) signaling, the Z3110 cells were pre-incubated for 1 h with respective inhibitors. These inhibitors were also added to the culture media when the cells were exposed to TNF-α (5 ng/ml) or a combination of TNF-α (5 ng/ml) and AVP (1 nM) for an additional hour. Note that the selective JNK inhibitor SP600125 completely abolished the induction of CXCL1 synthesis observed in response to TNF-α alone or to a combination of TNF-α and AVP. A selective MEK1 inhibitor PD-98059 partially (by >50%) inhibited CXCL1 synthesis, whereas p38 inhibitor SB203580 had no effect. In comparison, the inhibition of NF-κB signaling resulted in the amplification of chemokine synthesis. *p<0.05, **p<0.01 for treatment versus control. †p<0.05, ††p<0.01 for the incubation with inhibitor versus the incubation without inhibitor (n = 3 per group).
Mentions: To identify the signal transduction pathways mediating AVP action on the choroidal epithelium, we used selective inhibitors of JNK, MEK1, and p38. In the cultures of the Z310 cells, the inhibition of JNK completely abolished an increase in CXCL1 expression observed in response to either TNF-α or a combination of TNF-α and AVP (Fig. 4). The inhibition of ERK signaling only partially reduced the production of CXCL1, whereas the inhibition of p38 had no effect on chemokine synthesis. Interestingly, the inhibition of NF-κB signaling actually increased the synthesis of CXCL1 by the choroidal epithelium.

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