135. Simultaneous and complementary pro- and anti-inflammatory responses of immune stimulation by CpG-C

Abstract

Pro-(e.g., IL-12) and anti-inflammatory (e.g., IL-10) cytokines are believed to activate opposite responses and to be mutually inhibitory. The immunostimulatory agent CpG-C induces the production of IL-12, which activates NK cells. In the current study we tested the impact of CpG-C in conjunction with anti-IL-10 administration, conducting both in vitro and in vivo studies in rats, assessing cytokine levels, their induced production, and an in vivo NK-sensitive index– MADB106 lung tumor retention (LTR). Rats were inoculated with CpG-C, with or without anti-IL-10. Lungs and liver perfusates, and blood were collected 4 h later for the assessment of plasma and induced-production cytokine levels. Additionally, MADB106 cells were i.v. inoculated, and twenty hours later LTR was assessed. In vitro , CpG-C elevated IL-1 beta, IL-6, and IL-12, but interestingly also IL-10 levels, and anti-IL-10 further increased the production of the proinflammatory cytokines, especially in lungs and liver perfusates. In vivo , CpG-C administration increased NK activity and reduced MADB106 LTR, as expected, but surprisingly, anti-IL-10 worsened LTR in a dose dependent manner. We thus hypothesize that pro and anti inflammatory cytokines also have complementary in vivo effects, and that a simultaneous increase in their levels could be advantageous, specifically with respect to LTR/NK activity. The concomitant elevation of IL-12 and IL-10 by CpG-C possibly ensures a balance between pro and anti-inflammatory responses, limiting inflammatory damages, while maintaining immune activation.