The effects of interleukin-6 signal blockade on fertility, embryo-fetal development, and immunization in vivo

Birth Defects Res B Dev Reprod Toxicol. 2012 Aug;95(4):304-17. doi: 10.1002/bdrb.21019. Epub 2012 Jul 5.

Abstract

Possible effects of interleukin-6 (IL-6) on reproductive performance, embryonal development, parturition, and postnatal development have been suggested based on protein/mRNA expression 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-Il6(tm1Kopf)/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.

MeSH terms

  • Animals
  • Animals, Newborn
  • Antibodies, Neutralizing / administration & dosage
  • Antibodies, Neutralizing / blood
  • Antibodies, Neutralizing / pharmacology
  • Antibody Affinity / immunology
  • Body Weight / drug effects
  • Bone and Bones / drug effects
  • Crosses, Genetic
  • Embryo, Mammalian / drug effects
  • Embryo, Mammalian / metabolism
  • Embryonic Development / drug effects*
  • Female
  • Fertility / drug effects*
  • Fetus / drug effects*
  • Fetus / embryology*
  • Immunization*
  • Injections, Intravenous
  • Interleukin-6 / antagonists & inhibitors*
  • Interleukin-6 / deficiency
  • Interleukin-6 / metabolism
  • Lactation
  • Male
  • Memory / drug effects
  • Mice
  • Mice, Knockout
  • Milk / metabolism
  • Placenta / drug effects
  • Placenta / metabolism
  • Pregnancy
  • Rats
  • Reflex / drug effects
  • Serum Amyloid A Protein / metabolism
  • Signal Transduction / drug effects*

Substances

  • Antibodies, Neutralizing
  • Interleukin-6
  • Serum Amyloid A Protein