The Effects of Interleukin‐6 Signal Blockade on Fertility, Embryo‐fetal Development, and Immunization In vivo

Wiley - Tập 95 Số 4 - Trang 304-317 - 2012
Takayuki Sakurai1, Ryo Takai1, Heinrich Bürgin2, Kana Ishihara1, Yuichiro Sakamoto1, Jun Amano1, Yoshinobu Higuchi1, Shuichi Chiba1, Thomas P. Singer2, Akinori Kawamura3, Masami Suzuki1, Lutz Müller2
1Fuji Gotemba Research Labs, Chugai Pharmaceutical Co., Ltd, Shizuoka, Japan
2Non‐Clinical Safety Pharma Research and Early Development F. Hoffmann‐La Roche Ltd. Basel Switzerland
3Primary Lifecycle Management Department, Chugai Pharmaceutical Co, Ltd, Tokyo, Japan

Tóm tắt

Possible effects of interleukin‐6 (IL‐6) on reproductive performance, embryonal development, parturition, and postnatal development have been suggested based on protein/mRNAexpression level of IL‐6 in related organs, but less is known about functions of IL‐6 signals in these areas. Following two different approaches have been employed to investigate the role of IL‐6 signals in fertility and pre‐/postnatal development: administration of a rat anti‐mouse IL‐6 receptor antibody, MR16‐1, to mice as a neutralizing antibody system, and B6.129S2‐Il6tm1Kopf/J (IL‐6 knockout [KO]) mice as a KO system. By intravenously dosing 50 mg/kg of MR16‐1 every 3 days, animals in male and female fertility studies and dams in a pre‐/postnatal development study exhibited plasma MR16‐1 concentrations much higher than the effective plasma concentration, indicating that MR16‐1 exposure was sufficient to completely block IL‐6 signals. The concentration of MR16‐1 in the plasma of fetuses exceeded that in the plasma of pregnant animals, and MR16‐1 concentration in milk was about one‐fourth of that in plasma. Both the transient IL‐6 signal blockade by MR16‐1, and the constitutive IL‐6 signal inhibition using IL‐6 KO mice in a combined fertility and pre‐/postnatal development study, revealed no biologically important effects on fertility, early embryonic development to implantation, or pre‐/postnatal development, including IgG/IgM production by keyhole limpet hemocyanin sensitization. These results indicate that IL‐6 signals have no unique, noncompensable roles in reproduction and development in the whole body system, although contributions of IL‐6 in the signaling network appear to exist, as suggested by previously published investigations.

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Wiley

Tập 95 Số 4

304-317

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