Therapeutic effect of IL-12/23 and their signaling pathway blockade on brain ischemia model

Fumie Konoeda, Takashi Shichita, Hideyuki Yoshida, Yuki Sugiyama, Go Muto, Eiichi Hasegawa, Rinpei Morita, Norihiro Suzuki, Akihiko Yoshimura

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Recently, T cell cytokines such as IL-17 and IFN-γ have been shown to play important roles in the progression of brain injury induced by ischemia. We have shown that IL-23 from infiltrated macrophages activates γδT cells, thereby inducing IL-17 from these cells. However, deletion of the IL-23 gene in mice showed a more dramatic protective effect against brain ischemia reperfusion (I/R) model than γδT cell depletion did, suggesting that IL-23 plays some other pivotal role in brain injury in addition to its role in IL-17 induction. To develop therapeutic methods based on these findings, we examined the effect of the JAK kinase inhibitor CP-690550 and an anti-IL12/23 monoclonal antibody on an I/R model. CP-690550 efficiently inhibited IL-17 production from memory T cells in vitro and partly suppressed infarct volume increase after I/R. Anti-p40 antibody, which blocks both IL-12 and IL-23, efficiently suppressed I/R injury and improved recovery of neurological deficits. The number of IL-17-producing cells was decreased by anti-p40 antibody treatment. Thus the JAK inhibitor and anti-p40 antibody, both of which have already been under trial for the treatment of several human inflammatory diseases, appear to be promising therapeutic agents for the amelioration of stroke.

Original languageEnglish
Pages (from-to)500-506
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume402
Issue number3
DOIs
Publication statusPublished - 2010 Nov 19

Fingerprint

Brain models
Interleukin-23
Interleukin-17
Therapeutic Uses
Interleukin-12
Brain Ischemia
T-cells
T-Lymphocytes
Anti-Idiotypic Antibodies
Brain
Brain Injuries
Reperfusion
Antibodies
Ischemia
Janus Kinases
Macrophages
Reperfusion Injury
Genes
Stroke
Monoclonal Antibodies

Keywords

  • Anti-IL12p40 antibody
  • Brain ischemia
  • CP-690550
  • IL-17
  • JAK3 inhibitor

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology

Cite this

Therapeutic effect of IL-12/23 and their signaling pathway blockade on brain ischemia model. / Konoeda, Fumie; Shichita, Takashi; Yoshida, Hideyuki; Sugiyama, Yuki; Muto, Go; Hasegawa, Eiichi; Morita, Rinpei; Suzuki, Norihiro; Yoshimura, Akihiko.

In: Biochemical and Biophysical Research Communications, Vol. 402, No. 3, 19.11.2010, p. 500-506.

Research output: Contribution to journalArticle

Konoeda, F, Shichita, T, Yoshida, H, Sugiyama, Y, Muto, G, Hasegawa, E, Morita, R, Suzuki, N & Yoshimura, A 2010, 'Therapeutic effect of IL-12/23 and their signaling pathway blockade on brain ischemia model', Biochemical and Biophysical Research Communications, vol. 402, no. 3, pp. 500-506. https://doi.org/10.1016/j.bbrc.2010.10.058
Konoeda, Fumie ; Shichita, Takashi ; Yoshida, Hideyuki ; Sugiyama, Yuki ; Muto, Go ; Hasegawa, Eiichi ; Morita, Rinpei ; Suzuki, Norihiro ; Yoshimura, Akihiko. / Therapeutic effect of IL-12/23 and their signaling pathway blockade on brain ischemia model. In: Biochemical and Biophysical Research Communications. 2010 ; Vol. 402, No. 3. pp. 500-506.
@article{8217f79c7a464720984cf015ccecb7f7,
title = "Therapeutic effect of IL-12/23 and their signaling pathway blockade on brain ischemia model",
abstract = "Recently, T cell cytokines such as IL-17 and IFN-γ have been shown to play important roles in the progression of brain injury induced by ischemia. We have shown that IL-23 from infiltrated macrophages activates γδT cells, thereby inducing IL-17 from these cells. However, deletion of the IL-23 gene in mice showed a more dramatic protective effect against brain ischemia reperfusion (I/R) model than γδT cell depletion did, suggesting that IL-23 plays some other pivotal role in brain injury in addition to its role in IL-17 induction. To develop therapeutic methods based on these findings, we examined the effect of the JAK kinase inhibitor CP-690550 and an anti-IL12/23 monoclonal antibody on an I/R model. CP-690550 efficiently inhibited IL-17 production from memory T cells in vitro and partly suppressed infarct volume increase after I/R. Anti-p40 antibody, which blocks both IL-12 and IL-23, efficiently suppressed I/R injury and improved recovery of neurological deficits. The number of IL-17-producing cells was decreased by anti-p40 antibody treatment. Thus the JAK inhibitor and anti-p40 antibody, both of which have already been under trial for the treatment of several human inflammatory diseases, appear to be promising therapeutic agents for the amelioration of stroke.",
keywords = "Anti-IL12p40 antibody, Brain ischemia, CP-690550, IL-17, JAK3 inhibitor",
author = "Fumie Konoeda and Takashi Shichita and Hideyuki Yoshida and Yuki Sugiyama and Go Muto and Eiichi Hasegawa and Rinpei Morita and Norihiro Suzuki and Akihiko Yoshimura",
year = "2010",
month = "11",
day = "19",
doi = "10.1016/j.bbrc.2010.10.058",
language = "English",
volume = "402",
pages = "500--506",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Academic Press Inc.",
number = "3",

}

TY - JOUR

T1 - Therapeutic effect of IL-12/23 and their signaling pathway blockade on brain ischemia model

AU - Konoeda, Fumie

AU - Shichita, Takashi

AU - Yoshida, Hideyuki

AU - Sugiyama, Yuki

AU - Muto, Go

AU - Hasegawa, Eiichi

AU - Morita, Rinpei

AU - Suzuki, Norihiro

AU - Yoshimura, Akihiko

PY - 2010/11/19

Y1 - 2010/11/19

N2 - Recently, T cell cytokines such as IL-17 and IFN-γ have been shown to play important roles in the progression of brain injury induced by ischemia. We have shown that IL-23 from infiltrated macrophages activates γδT cells, thereby inducing IL-17 from these cells. However, deletion of the IL-23 gene in mice showed a more dramatic protective effect against brain ischemia reperfusion (I/R) model than γδT cell depletion did, suggesting that IL-23 plays some other pivotal role in brain injury in addition to its role in IL-17 induction. To develop therapeutic methods based on these findings, we examined the effect of the JAK kinase inhibitor CP-690550 and an anti-IL12/23 monoclonal antibody on an I/R model. CP-690550 efficiently inhibited IL-17 production from memory T cells in vitro and partly suppressed infarct volume increase after I/R. Anti-p40 antibody, which blocks both IL-12 and IL-23, efficiently suppressed I/R injury and improved recovery of neurological deficits. The number of IL-17-producing cells was decreased by anti-p40 antibody treatment. Thus the JAK inhibitor and anti-p40 antibody, both of which have already been under trial for the treatment of several human inflammatory diseases, appear to be promising therapeutic agents for the amelioration of stroke.

AB - Recently, T cell cytokines such as IL-17 and IFN-γ have been shown to play important roles in the progression of brain injury induced by ischemia. We have shown that IL-23 from infiltrated macrophages activates γδT cells, thereby inducing IL-17 from these cells. However, deletion of the IL-23 gene in mice showed a more dramatic protective effect against brain ischemia reperfusion (I/R) model than γδT cell depletion did, suggesting that IL-23 plays some other pivotal role in brain injury in addition to its role in IL-17 induction. To develop therapeutic methods based on these findings, we examined the effect of the JAK kinase inhibitor CP-690550 and an anti-IL12/23 monoclonal antibody on an I/R model. CP-690550 efficiently inhibited IL-17 production from memory T cells in vitro and partly suppressed infarct volume increase after I/R. Anti-p40 antibody, which blocks both IL-12 and IL-23, efficiently suppressed I/R injury and improved recovery of neurological deficits. The number of IL-17-producing cells was decreased by anti-p40 antibody treatment. Thus the JAK inhibitor and anti-p40 antibody, both of which have already been under trial for the treatment of several human inflammatory diseases, appear to be promising therapeutic agents for the amelioration of stroke.

KW - Anti-IL12p40 antibody

KW - Brain ischemia

KW - CP-690550

KW - IL-17

KW - JAK3 inhibitor

UR - http://www.scopus.com/inward/record.url?scp=78549273305&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78549273305&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2010.10.058

DO - 10.1016/j.bbrc.2010.10.058

M3 - Article

VL - 402

SP - 500

EP - 506

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 3

ER -