TNF- -Independent IL-8 Expression: Alterations in Bacterial Challenge Dose Cause Differential Human Monocytic Cytokine Response

We examined the effects of different bacterial doses of Neisseria gonorrhoeae on the cytokine response of primary human monocytes. The data indicate that a low multiplicity of infection (MOI) challenge (MOI 0.1) results in substantial production of IL-8 and other chemokines/cytokines, in the absence of significant TNFproduction. Positive control challenges (MOI 10) induced levels of IL-8 that were comparable to the low MOI challenges, but now induced significant levels of TNF. Induction of IL-8 expression in low MOI challenges was not mediated by an autocrine response as pretreatment of monocytes with neutralizing Abs against TNFor IL-1 had no effect on IL-8 expression. IL-8 induction resulting from gonococcal challenge was shown to require NFB activation, though this activation was limited by the inoculating dose. These data indicate that IL-8 induction results from direct contact between bacteria and monocytes. Analysis of the overall cytokine profile revealed patterns of expression for growthregulated oncogene, MCP-1, and IL-6 that were similar to IL-8. Analysis of various MAPKs indicated that low MOI challenges were able to efficiently activate both the ERK and p38 pathways, but in contrast to positive control samples, failed to activate the JNK pathway. A lack of phosphorylated JNK leads to decreased production of AP-1 dimers, transcription factors that are critical for efficient transcription of TNF. Therefore, we propose a mechanism where a low MOI gonococcal challenge results in diminished AP-1 activity and TNFproduction while IL-8 levels remain constant. The Journal of Immunology, 2006, 177: 1314–1322.