The Toll-like receptor 1/2 agonists Pam3CSK4 and human β-defensin-3 differentially induce interleukin-10 and nuclear factor-κB signalling patterns in human monocytes

Human beta-defensin 3 (hBD-3) activates antigen-presenting cells through Toll-like receptors (TLRs) 1/2. Several TLR1/2 agonists have been identified but little is known about how they might differentially affect cellular activation. We compared the effects of hBD-3 with those of another TLR1/2 agonist, Pam(3)CSK(4), in human monocytes. Monocytes incubated with hBD-3 or Pam(3)CSK(4) produced interleukin-6 (IL-6), IL-8 and IL-1 beta, but only Pam(3)CSK(4) induced IL-10. The IL-10 induction by Pam(3)CSK(4) caused down-modulation of the co-stimulatory molecule, CD86, whereas CD86 expression was increased in monocytes exposed to hBD-3. Assessment of signalling pathways linked to IL-10 induction indicated that mitogen- activated protein kinases were activated similarly by hBD-3 or Pam(3)CSK(4), whereas the non-canonical nuclear factor-kappa B pathway was only induced by Pam(3)CSK(4). Our data suggest that the lack of non-canonical nuclear factor-kappa B signalling by hBD-3 could contribute to the failure of this TLR agonist to induce production of the anti-inflammatory cytokine, IL-10, in human monocytes.