I Kappa B Zeta Regulates Human Monocyte Pro-Inflammatory Responses Induced By Streptococcus Pneumoniae

Pneumococcal lung infections represent a major cause of death worldwide. Single nucleotide polymorphisms (SNPs) in the NFKBIZ gene, encoding the transcription factor I kappa B zeta, are associated with increased susceptibility to invasive pneumococcal disease. We hence analyzed how I kappa B zeta might regulate inflammatory responses to pneumococcal infection. We first demonstrate that I kappa B zeta is expressed in human blood monocytes but not in bronchial epithelial cells, in response to wild type pneumococcal strain D39. D39 transiently induced I kappa B zeta in a dose dependent manner, with subsequent induction of downstream molecules involved in host defense. Of these molecules, I kappa B zeta knockdown reduced the expression of IL-6 and GMCSF. Furthermore, I kappa B zeta overexpression increased the activity of IL-6 and GMCSF promoters, supporting the knockdown findings. Pneumococci lacking either pneumolysin or capsule still induced I kappa B zeta. While inhibition of TLR1/TLR2 blocked D39 induced I kappa B zeta expression, TLR4 inhibition did not. Blockade of p38 MAP kinase and NF kappa B suppressed D39 induced I kappa B zeta. Overall, our data demonstrates that I.B. regulates monocyte inflammatory responses to Streptococcus pneumoniae by promoting the production of IL-6 and GMCSF.