title: Antitumor effect of humanized anti-interleukin-6 receptor antibody (tocilizumab) on glioma cell proliferation. Laboratory investigation.
abstract: OBJECTIVE
  Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates diverse physiological functions, including cell proliferation and survival. Recent studies have shown that IL-6 expression is often elevated in response to several types of glioma. Although IL-6 is said to play an important role in glioma, the involvement of IL-6 signaling has been quite controversial. The aim of this study was to evaluate the involvement of IL-6 signaling in glioma and the inhibitory effect of IL-6 signaling on glioma tumor proliferation.
  
  
  METHODS
  The expression of IL-6 receptors (IL-6Rs) was evaluated in glioma tissues by means of immunohistochemical analysis, and the involvement of IL-6 signaling in glioblastoma multiforme (GBM) U87MG cell proliferation was also determined. In addition, to examine the inhibitory effect of IL-6 signaling on glioma cell proliferation, the authors investigated the effects of tocilizumab, the humanized anti-human IL-6R antibody in U87MG cells.
  
  
  RESULTS
  Increased immunoreactivity for IL-6R was predominantly found in the cytoplasm of endothelial cells in all GBM samples. Inhibition of IL-6 signaling by both IL-6- and IL-6R-specific small interfering RNA and AG490, a specific inhibitor of JAK2 phosphorylation, suppressed glioma cell proliferation. Furthermore, tocilizumab, a clinically developed humanized anti-human IL-6R antibody, exerted an antiproliferative effect on cells from the GBM cell line U87MG via the IL-6R-dependent JAK-STAT3 pathway.
  
  
  CONCLUSIONS
  The IL-6 signaling pathway plays an important role in glioma cell proliferation, and tocilizumab exerts an antitumor effect in U87MG glioma cells. These results may bring new insight into the molecular pathogenesis of glioma and may lead to a new therapeutic intervention.
authors.affiliation: Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Mareina
authors.initials: M
authors.lastname: Kudo
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Jono
authors.forename: Satoru
authors.initials: S
authors.lastname: Shinriki
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Yano
authors.forename: Hideo
authors.initials: H
authors.lastname: Nakamura
authors.forename: Keishi
authors.initials: K
authors.lastname: Makino
authors.forename: Takuichiro
authors.initials: T
authors.lastname: Hide
authors.forename: Daisuke
authors.initials: D
authors.lastname: Muta
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Ueda
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Ota
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ando
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Kuratsu