In this study, we investigated the role of toll-like receptor (TLR) and mitogen-activated protein kinase (MAPK) pathways involved in the tumor necrosis factor (TNF)-${alpha}$ and interleukin (IL)-6 expression after stimulation with purified protein derivatives (PPD) or native 38-kDa protein antigen (Ag) of Mycobacterium tuberculosis H37Rv in human primary monocytes. Both PPD and 38-kDa Ag significantly induced TNF-${alpha}$ and IL-6 in human primary monocytes. MAPK [extracellular signal-regulated kinase (ERK) 1/2 and p38] are rapidly phosphorylated in human monocytes stimulated with the PPD or 38-kDa Ag. Both p38 and ERK 1/2 activation are essential for PPD- or 38-kDa-induced TNF-${alpha}$ and IL-6 production. The inhibition of TLR2 and TLR4 by specific antibodies significantly abrogated the 38-kDa-induced secretion of TNF-${alpha}$ and IL-6, whereas blockade of TLR2, but not TLR4, was responsible for the PPD-induced TNF-${alpha}$ and IL-6 production in human monocytes. Collectively, these data suggest that the PPD and 38-kDa Ag differentially interact with TLR2 and TLR4, which in turn mediate an essential role for the early inflammatory immune responses during human tuberculosis.