We previously demonstrated that HIV-1 core protein p24 directly induced human monocytic production of TNF-${alpha}$ and MMP-9. Present study was conducted to further elucidate the intracellular pathways involved and evaluate the direct effect and the underlying mechanism of various protein kinase (PK) inhibitors on this p24 specific inflammatory response. Tyrosine kinase (TK) inhibitor genistein, effectively suppressed p24-induced TNF-${alpha}$ production, which was largely coincided with the down-regulation of MMP-9 production. Similar inhibitory action was also exerted by phosphatidylinositol 3-kinase (PI(3)K) inhibitor LY294002 or to a lesser extent by PKC inhibitor H7. Results of mechanistic study revelaed that nuclear factor-kappaB (NF-${kappa}B$) was activated by p24 stimulation and that the cellular action of these PK inhibitors was mediated at least in part through the negative modulation of NF-${kappa}B$ DNA pathway. These observations support that HIV-1 core antigen p24 has the capacity to elicit NF-${kappa}B$ activation through multiple signaling cascades for induction of human monocytic TNF-${alpha}$ which in its turn to lead to MMP-9 production in an autocrine manner. Accordingly, blockade of NF-${kappa}B$ activation by the inhibitors of various signaling pathways implicated may represent potential therapeutic targets for the control of HIV-1 associated neurological damage.