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[kappa]B[zeta] regulates monocyte inflammatory responses to Streptococcus pneumoniae by promoting the production of IL-6 and GMCSF.