Signaling through interleukin-6 receptor supports blast cell proliferation in acute myeloblastic leukemia

Hyperlipidemia has been demonstrated to be associated with renal disease, yet the mechanism of renal injury is still poorly understood. Inflammation that occurs with the hyperlipidemia has been considered to play an important role in development of glomerular injury. In the present study, we investigated the role of interleukin-6 (IL-6), a key inflammatory molecule, on renal injury in apolipoprotein E-deficient (ApoE−/−) mice with severe hypercholesterolemia. The 6-wk-old mice were fed a high-fat diet and administered weekly rat anti-IL-6 receptor monoclonal antibody (MR16-1), control rat IgG, or saline for a total of 4 wk. We examined histopathological changes in the kidney and urinary excretion of protein and albumin. Saline- and IgG-treated mice showed remarkable proteinuria at 10 wk of age, whereas MR16-1-treated mice exhibited significantly lower levels. Renal histopathology of saline- and IgG-treated mice revealed striking lipid deposits and foam cells in the glomerular tuft, juxtaglomerular area, and arteriolar wall along with range of mesangial cell proliferation and matrix expansion. Notably, the severity of lipid deposits and mesangial cell proliferation were significantly reduced in MR16-1-treated mice. Immunohistochemistry demonstrated that mesangial IL-6 expression was dramatically reduced in MR16-1-treated mice compared with IgG-treated mice. Blocking the IL-6 receptor prevented progression of proteinuria and renal lipid deposit, as well as the mesangial cell proliferation associated with severe hyperlipoproteinemia. These results clearly demonstrate that IL-6 plays an essential role in the pathogenesis of hyperlipidemia-induced glomerular injury in ApoE−/− mice and suggests the usefulness of anti-IL-6 receptor antibody in treatments for hyperlipidemia-induced organ damage.

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Antitumor effect of humanized anti–interleukin-6 receptor antibody (tocilizumab) on glioma cell proliferation

Journal of Neurosurgery ◽

10.3171/2008.12.jns081284 ◽

2009 ◽

Vol 111 (2) ◽

pp. 219-225 ◽

Cited By ~ 33

Author(s):

Mareina Kudo ◽

Hirofumi Jono ◽

Satoru Shinriki ◽

Shigetoshi Yano ◽

Hideo Nakamura ◽

...

Keyword(s):

Cell Proliferation ◽

Interleukin 6 ◽

Glioma Cell ◽

Antitumor Effect ◽

Specific Inhibitor ◽

Immunohistochemical Analysis ◽

Inhibitory Effect ◽

Interleukin 6 Receptor ◽

Glioma Cell Proliferation ◽

Interfering Rna

Object 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.

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