Anti-IL-6 receptor antibody increases blood IL-6 level via the blockade of IL-6 clearance, but not via the induction of IL-6 production

Uchiyama, Yasushi; Yoshida, Hiroto; Koike, Nobuo; Hayakawa, Naohiko; Sugita, Atsuko; Nishimura, Takashi; Mihara, Masahiko

doi:10.1016/j.intimp.2008.07.002

Cited by 41 publications

(33 citation statements)

References 16 publications

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“…1B). As reported previously (16), the level of IL-6 elevated after the initiation of tocilizumab therapy, however, the level of IL-18 remained extremely high (more than 5,000 pg/mL, Fig. 1C).…”

Section: Case Reportsupporting

confidence: 85%

Tocilizumab Improved both Clinical and Laboratory Manifestations Except for Interleukin-18 in a Case of Multiple Drug-Resistant Adult-Onset Still's Disease

et al. 2011

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A patient with adult-onset Still's disease (AOSD) resistant to multiple drugs was treated in our hospital. Even biologics that block tumor necrosis factor (TNF) were ineffective. However, this patient responded quite well to tocilizumab, an interleukin (IL)-6 receptor blocker, suggesting that it is among the promising candidate drugs for multiple-drug resistant AOSD. Although the serum levels of most inflammatory markers such as C-reactive protein (CRP) and ferritin were reduced promptly by tocilizumab, that of IL-18 remained high. Thus, IL-18 is considered to have a further upstream position than IL-6 or to be at the same level as IL-6 in the inflammatory cascade of AOSD. This finding casts light on the pathogenesis of AOSD, and drugs that target IL-18 may prove beneficial in the treatment of this inflammatory disease.

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Section: Case Reportsupporting

confidence: 85%

Tocilizumab Improved both Clinical and Laboratory Manifestations Except for Interleukin-18 in a Case of Multiple Drug-Resistant Adult-Onset Still's Disease

et al. 2011

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“…Expectedly, plasma IL-6 levels were greatly elevated but, in contrast, plasma SAA levels were suppressed by MR16-1 treatment in MCD diet-fed db/db mice 24 (Figures 3a and b). These observations suggested that MR16-1 treatment blocked the IL-6 receptor successfully.…”

Section: An MCD Diet Suppressed Il-6 Signaling With Downregulation Ofmentioning

confidence: 97%

Blockade of IL-6 signaling exacerbates liver injury and suppresses antiapoptotic gene expression in methionine choline-deficient diet-Fed db/db mice

Yamaguchi

Itoh

Yokomizo

et al. 2011

Laboratory Investigation

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Our previous study revealed that blockade of interleukin-6 (IL-6)-STAT3 signaling ameliorated liver injury, although hepatic STAT3 À/À or GP130 À/À mice have been reported to develop severe liver injury, in a murine methionine choline deficient (MCD) diet-induced model of non-alcoholic steatohepatitis (NASH). In this study, to determine whether profound blockade of IL-6-STAT3 signaling may still ameliorate liver injury, we studied db/db mice, which have impaired leptin-mediated STAT3 activation, using the MCD diet-induced NASH model. Male lean and db/db mice (6 weeks old) were fed either control chow or an MCD diet for 8 or 12 weeks. Half of the mice were treated with 15 mg/kg rat anti-mouse IL-6 receptor neutralizing antibody (MR16-1) intraperitoneally twice weekly, the remainder were injected with 15 mg/kg rat IgG as a control. Hepatic steatosis, injury, fibrosis, markers of lipid peroxidation/oxidant stress and antiapoptotic gene expression were evaluated. Plasma IL-6 levels were elevated in all groups of db/db mice. Although hepatic IL-6/ GP130 signaling was activated in chow-fed db/db mice, this was suppressed in MCD diet-fed db/db mice, accompanied by downregulation of hepatic IL-6 receptor and GP130 mRNA expression. MR16-1 treatment of MCD dietfed db/db mice further repressed STAT3 activities and expression of STAT3-related antiapoptotic genes, such as Bcl-2 and Ref-1, but increased plasma-free fatty acid and hepatic markers of lipid peroxidation/oxidant stress, leading to increased liver injury, hepatocyte apoptosis and liver fibrosis. Although 'moderate' blockade of enhanced IL-6-STAT3 signaling may be beneficial in NASH, as we reported previously, these findings demonstrate that a profound defect in STAT3 activation is detrimental in terms of liver injury, hepatocyte apoptosis and liver fibrosis, indicating the hepato-protective role of IL-6 signaling in this severe NASH model.

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“…24 First, to examine the efficacy of MR16-1, we measured plasma IL-6 concentrations after MR16-1 treatment, and found that plasma IL-6 levels were greatly increased. This phenomenon may be caused by decreased clearance of IL-6 from the blood 28 and suggests that MR16-1 treatment blocked the IL-6 receptor successfully (Figure 2a, Supplementary Figure 1A). This treatment had little effect on STAT3 phosphorylation in chow-fed controls but greatly decreased MCD diet-induced STAT3 phosphorylation (Figure 2b, Supplementary Figure 1B).…”

Section: An MCD Diet Elevated Plasma Il-6 Levels and Activated Hepatimentioning

confidence: 99%

Blockade of interleukin-6 signaling enhances hepatic steatosis but improves liver injury in methionine choline-deficient diet-fed mice

Yamaguchi

Itoh

Yokomizo

et al. 2010

Laboratory Investigation

101

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Inflammatory processes have an important role in the development of hepatic steatosis and progression to nonalcoholic steatohepatitis (NASH). Interleukin-6 (IL-6) is known to be a proinflammatory cytokine, but also promotes liver regeneration and protects the liver against various forms of damage. The role of IL-6/Glycoprotein130 (GP130) in NASH remains unclear. In this study, we determined whether blocking IL-6/GP130 signaling prevents progression of steatohepatitis in a mouse NASH model. Six-week-old male C57/BL6 mice were fed either chow control or a methionine cholinedeficient (MCD) diet for 8 weeks. Half of the MCD diet-fed mice were treated with 15 mg/kg rat anti-mouse IL-6 receptor antibody (MR16-1), intraperitoneally twice weekly, the remainder and chow-fed mice were injected with 15 mg/kg rat IgG as a control. Hepatic steatosis, injury, fibrosis, apoptosis, markers of lipid peroxidation/oxidant stress and IL-6-related gene expressions were evaluated. MR16-1 treatment decreased signal transducer and activator of transcription 3 activities and expression of suppressor of cytokine signaling 3 in MCD diet-treated mouse livers. Although this treatment enhanced intrahepatic lipid accumulation accompanied by increased sterol regulatory element-binding protein 1 and decreased peroxisome proliferator-activated receptor-a expression, elevated plasma alanine aminotransferase levels were improved with decreased plasma free fatty acid levels, lipid peroxidation/oxidant stress and hepatic apoptosis. Blocking IL-6/GP130 signaling by MR16-1 enhanced MCD diet-induced hepatic steatosis, but ameliorated liver injury. These findings suggest that hepatic IL-6 signaling has a protective role against the progression of hepatic steatosis but may enhance liver inflammation.

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Anti-IL-6 receptor antibody increases blood IL-6 level via the blockade of IL-6 clearance, but not via the induction of IL-6 production

Cited by 41 publications

References 16 publications

Tocilizumab Improved both Clinical and Laboratory Manifestations Except for Interleukin-18 in a Case of Multiple Drug-Resistant Adult-Onset Still's Disease

Tocilizumab Improved both Clinical and Laboratory Manifestations Except for Interleukin-18 in a Case of Multiple Drug-Resistant Adult-Onset Still's Disease

Blockade of IL-6 signaling exacerbates liver injury and suppresses antiapoptotic gene expression in methionine choline-deficient diet-Fed db/db mice

Blockade of interleukin-6 signaling enhances hepatic steatosis but improves liver injury in methionine choline-deficient diet-fed mice

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