Toll-like receptor-2 (TLR2) is one of the important innate immune receptors that play an important role in recognizing the pathogens and producing inflammatory cytokines. In this review, we focus on the regulatory mechanisms of expression, function and inflammatory responses of TLR2 during pathogenic infection in innate immune cells. We first showed that nontypeable Haemophilus influenzae (NTHi), an important human pathogen that exacerbates otitis media and chronic obstructive pulmonary diseases (COPD), induces inflammatory responses through activation of NF-κB via two distinct signals, NIK-IKKα/β-IκBα and MKK3/6-p38 pathways. Moreover, TLR2 was greatly up-regulated by NTHi through the positive IKK-IκBα-dependent NF-κB pathway and the negative MKK3/6-p38α/β pathway. Importantly, glucocorticoids synergistically enhance NTHi-induced TLR2 up-regulation likely via a negative cross-talk with the inhibitory p38 MAPK. The results provide novel insights into the role of glucocorticoids in regulating host defense and innate immune responses through TLR2 regulation. We next focused on the pathogenesis of cystic fibrosis (CF), a common lethal inherited disorder characterized by recurrent pulmonary infections and obstruction caused by chronic mucus hypersecretion and inflammation. We demonstrated an increased expression of TLR2, due to an enhanced DNA de-methylation and Sp1-dependent transcriptional activation in CF epithelial cells. Furthermore, a Th17 cytokine IL-17A synergistically increased TLR2 signal through an enhancement of p38 phosphorylation. These studies suggest the importance of TLR2 and IL-17 signals in the pathogenesis of CF. Finally, by focusing on neutrophils and CF airway epithelial cells, we identified curcumin as a potent inhibitor of TLR2-mediated inflammatory responses.