IL-6 knockout mice are protected from cocaine-induced kindling behaviors; possible involvement of JAK2/STAT3 and PACAP signalings
- Authors
- Huynh Nhu Mai; Chung, Yoon Hee; Shin, Eun-Joo; Sharma, Naveen; Jeong, Ji Hoon; Jang, Choon-Gon; Saito, Kuniaki; Nabeshima, Toshitaka; Reglodi, Dora; Kim, Hyoung-Chun
- Issue Date
- Jun-2018
- Publisher
- PERGAMON-ELSEVIER SCIENCE LTD
- Keywords
- Cocaine-induced kindling (convulsive) behaviors; Interleukin-6 knockout mice; Pituitary adenylate cyclase-activating polypeptide; JAK2/STAT3; Tumor necrosis factor-alpha knockout mice; Hippocampus
- Citation
- FOOD AND CHEMICAL TOXICOLOGY, v.116, pp 249 - 263
- Pages
- 15
- Journal Title
- FOOD AND CHEMICAL TOXICOLOGY
- Volume
- 116
- Start Page
- 249
- End Page
- 263
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/2117
- DOI
- 10.1016/j.fct.2018.04.031
- ISSN
- 0278-6915
1873-6351
- 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-alpha expression, it resulted in a decrease in IFN-gamma expression. We observed that the cocaine-induced increase in IL-6 expression was more pronounced than that in TNF-alpha 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-alpha gene expression. TNF-alpha 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 mu g, 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-alpha gene to modulate its anticonvulsive/neuroprotective potential.
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