Salmonella typhi is an important human pathogen responsible for typhoid fever. Type IVB pili, encoded by the S. typhi pil operon located in the major pathogenicity island, are used to facilitate bacterial entry into human intestinal cells in vitro and may be important in the mediation of enteric fever in humans. However, possible involvement of the typeIVB pili of S. typhi in signal transduction in infected immune cells has not been examined previously. In this study, we have compared the effect of piliated and nonpiliated S. typhi on the activities of protein kinase C (PKC), the production of interleukin-6 (IL-6) and nuclear transcription factor NF-kB in human monocytic THP-1 cells. We find that piliated S. typhi can stimulate significantly higher activities of PKC, the production of IL-6 and NF-kB than a nonpiliated strain based on substrate phosphorolysis kinase assay,Western blot, RT-PCR, and luciferase reporter gene assay. In time course experiments, PKC activity increased in a time-dependent fashion after stimulation by the piliated bacteria. The PKC inhibitor Dequalinium chloride (DECA) remarkably reduced the production of IL-6, NF-kB and theacti vity of PKC induced by thepiliate d S. typhi. These results suggest that the induction of IL-6 and NF-kB depend on the PKC signal pathway. Our report demonstrates that the type IVB pili of S. typhi play important roles in the production of NF-kB and the proinflammatory cytokine IL-6, and in the stimulation of PKC activity and therefore, may have effects on the development of fever and other inflammatory responses.