IL-6 knockout mice are protected from cocaine-induced kindling behaviors; possible involvement of JAK2/STAT3 and PACAP signalings

Huynh Nhu Mai, Yoon Hee Chung, Eun Joo Shin, Naveen Sharma, Ji Hoon Jeong, Choon Gon Jang, Kuniaki Saito, Toshitaka Nabeshima, Dora Reglodi, Hyoung Chun Kim

Research output: Contribution to journalArticle

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Abstract

IL-6 has been recognized as an anticonvulsant against certain neuroexcitotoxicities. We aimed to investigate on the interactive role between IL-6 and PACAP in cocaine-induced kindling behaviors. Although we found that cocaine (45 mg/kg, i.p./day x 5) significantly increased IL-6 and TNF-α expression, it resulted in a decrease in IFN-γ expression. We observed that the cocaine-induced increase in IL-6 expression was more pronounced than that in TNF-α expression. Genetic depletion of IL-6 significantly activated cocaine kindling behaviors. This phenomenon was also consistently observed in WT mice that received a neutralizing IL-6 receptor antibody. Cocaine-treated IL-6 knockout mice exhibited significantly decreased PACAP and PACAP receptor (PAC1R) mRNA levels and significantly increased TNF-α gene expression. TNF-α knockout mice were protected from cocaine kindling via an up-regulation of IL-6, phospho-JAK2/STAT3, PACAP, and PAC1R levels, which produced anti-apoptotic effects. Recombinant IL-6 protein (rIL-6, 2 μg, i.v./mouse/day x 5) also up-regulated phospho-JAK2/STAT3, PACAP, and PAC1R mRNA levels, leading to anti-apoptotic effects in IL-6 knockout mice. Consistently, AG490, a JAK2/STAT3 inhibitor, and PACAP 6–38, a PAC1 receptor antagonist, counteracted rIL-6-mediated protection. Combined, our results suggest that IL-6 gene requires up-regulation of phospho-JAK2/STAT3, PACAP, and PAC1R and down-regulation of the TNF-α gene to modulate its anticonvulsive/neuroprotective potential.

Original languageEnglish
Pages (from-to)249-263
Number of pages15
JournalFood and Chemical Toxicology
Volume116
DOIs
Publication statusPublished - 01-06-2018

Fingerprint

Pituitary Adenylate Cyclase-Activating Polypeptide
cocaine
Cocaine
Knockout Mice
interleukin-6
Interleukin-6
mice
receptors
Up-Regulation
Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
Genes
Pituitary Adenylate Cyclase-Activating Polypeptide Receptors
Interleukin-6 Receptors
Messenger RNA
anticonvulsants
Gene expression
Anticonvulsants
neutralization
Down-Regulation
antagonists

All Science Journal Classification (ASJC) codes

  • Food Science
  • Toxicology

Cite this

Mai, Huynh Nhu ; Chung, Yoon Hee ; Shin, Eun Joo ; Sharma, Naveen ; Jeong, Ji Hoon ; Jang, Choon Gon ; Saito, Kuniaki ; Nabeshima, Toshitaka ; Reglodi, Dora ; Kim, Hyoung Chun. / IL-6 knockout mice are protected from cocaine-induced kindling behaviors; possible involvement of JAK2/STAT3 and PACAP signalings. In: Food and Chemical Toxicology. 2018 ; Vol. 116. pp. 249-263.
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abstract = "IL-6 has been recognized as an anticonvulsant against certain neuroexcitotoxicities. We aimed to investigate on the interactive role between IL-6 and PACAP in cocaine-induced kindling behaviors. Although we found that cocaine (45 mg/kg, i.p./day x 5) significantly increased IL-6 and TNF-α expression, it resulted in a decrease in IFN-γ expression. We observed that the cocaine-induced increase in IL-6 expression was more pronounced than that in TNF-α expression. Genetic depletion of IL-6 significantly activated cocaine kindling behaviors. This phenomenon was also consistently observed in WT mice that received a neutralizing IL-6 receptor antibody. Cocaine-treated IL-6 knockout mice exhibited significantly decreased PACAP and PACAP receptor (PAC1R) mRNA levels and significantly increased TNF-α gene expression. TNF-α knockout mice were protected from cocaine kindling via an up-regulation of IL-6, phospho-JAK2/STAT3, PACAP, and PAC1R levels, which produced anti-apoptotic effects. Recombinant IL-6 protein (rIL-6, 2 μg, i.v./mouse/day x 5) also up-regulated phospho-JAK2/STAT3, PACAP, and PAC1R mRNA levels, leading to anti-apoptotic effects in IL-6 knockout mice. Consistently, AG490, a JAK2/STAT3 inhibitor, and PACAP 6–38, a PAC1 receptor antagonist, counteracted rIL-6-mediated protection. Combined, our results suggest that IL-6 gene requires up-regulation of phospho-JAK2/STAT3, PACAP, and PAC1R and down-regulation of the TNF-α gene to modulate its anticonvulsive/neuroprotective potential.",
author = "Mai, {Huynh Nhu} and Chung, {Yoon Hee} and Shin, {Eun Joo} and Naveen Sharma and Jeong, {Ji Hoon} and Jang, {Choon Gon} and Kuniaki Saito and Toshitaka Nabeshima and Dora Reglodi and Kim, {Hyoung Chun}",
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IL-6 knockout mice are protected from cocaine-induced kindling behaviors; possible involvement of JAK2/STAT3 and PACAP signalings. / Mai, Huynh Nhu; Chung, Yoon Hee; Shin, Eun Joo; Sharma, Naveen; Jeong, Ji Hoon; Jang, Choon Gon; Saito, Kuniaki; Nabeshima, Toshitaka; Reglodi, Dora; Kim, Hyoung Chun.

In: Food and Chemical Toxicology, Vol. 116, 01.06.2018, p. 249-263.

Research output: Contribution to journalArticle

TY - JOUR

T1 - IL-6 knockout mice are protected from cocaine-induced kindling behaviors; possible involvement of JAK2/STAT3 and PACAP signalings

AU - Mai, Huynh Nhu

AU - Chung, Yoon Hee

AU - Shin, Eun Joo

AU - Sharma, Naveen

AU - Jeong, Ji Hoon

AU - Jang, Choon Gon

AU - Saito, Kuniaki

AU - Nabeshima, Toshitaka

AU - Reglodi, Dora

AU - Kim, Hyoung Chun

PY - 2018/6/1

Y1 - 2018/6/1

N2 - IL-6 has been recognized as an anticonvulsant against certain neuroexcitotoxicities. We aimed to investigate on the interactive role between IL-6 and PACAP in cocaine-induced kindling behaviors. Although we found that cocaine (45 mg/kg, i.p./day x 5) significantly increased IL-6 and TNF-α expression, it resulted in a decrease in IFN-γ expression. We observed that the cocaine-induced increase in IL-6 expression was more pronounced than that in TNF-α expression. Genetic depletion of IL-6 significantly activated cocaine kindling behaviors. This phenomenon was also consistently observed in WT mice that received a neutralizing IL-6 receptor antibody. Cocaine-treated IL-6 knockout mice exhibited significantly decreased PACAP and PACAP receptor (PAC1R) mRNA levels and significantly increased TNF-α gene expression. TNF-α knockout mice were protected from cocaine kindling via an up-regulation of IL-6, phospho-JAK2/STAT3, PACAP, and PAC1R levels, which produced anti-apoptotic effects. Recombinant IL-6 protein (rIL-6, 2 μg, i.v./mouse/day x 5) also up-regulated phospho-JAK2/STAT3, PACAP, and PAC1R mRNA levels, leading to anti-apoptotic effects in IL-6 knockout mice. Consistently, AG490, a JAK2/STAT3 inhibitor, and PACAP 6–38, a PAC1 receptor antagonist, counteracted rIL-6-mediated protection. Combined, our results suggest that IL-6 gene requires up-regulation of phospho-JAK2/STAT3, PACAP, and PAC1R and down-regulation of the TNF-α gene to modulate its anticonvulsive/neuroprotective potential.

AB - IL-6 has been recognized as an anticonvulsant against certain neuroexcitotoxicities. We aimed to investigate on the interactive role between IL-6 and PACAP in cocaine-induced kindling behaviors. Although we found that cocaine (45 mg/kg, i.p./day x 5) significantly increased IL-6 and TNF-α expression, it resulted in a decrease in IFN-γ expression. We observed that the cocaine-induced increase in IL-6 expression was more pronounced than that in TNF-α expression. Genetic depletion of IL-6 significantly activated cocaine kindling behaviors. This phenomenon was also consistently observed in WT mice that received a neutralizing IL-6 receptor antibody. Cocaine-treated IL-6 knockout mice exhibited significantly decreased PACAP and PACAP receptor (PAC1R) mRNA levels and significantly increased TNF-α gene expression. TNF-α knockout mice were protected from cocaine kindling via an up-regulation of IL-6, phospho-JAK2/STAT3, PACAP, and PAC1R levels, which produced anti-apoptotic effects. Recombinant IL-6 protein (rIL-6, 2 μg, i.v./mouse/day x 5) also up-regulated phospho-JAK2/STAT3, PACAP, and PAC1R mRNA levels, leading to anti-apoptotic effects in IL-6 knockout mice. Consistently, AG490, a JAK2/STAT3 inhibitor, and PACAP 6–38, a PAC1 receptor antagonist, counteracted rIL-6-mediated protection. Combined, our results suggest that IL-6 gene requires up-regulation of phospho-JAK2/STAT3, PACAP, and PAC1R and down-regulation of the TNF-α gene to modulate its anticonvulsive/neuroprotective potential.

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