Biol. Pharm. Bull. 30(9) 1617—1623 (2007)

The innate immune system is the first line of host defense against infectious microbes. Toll-like receptors (TLRs) are a family of receptors that trigger innate immune reactions in response to various microbial products, such as lipopolysaccharide (LPS), flagellin, double-stranded RNA, CpG-DNA, and others. Stimulation of TLRs leads to the activation and maturation of antigen-presenting cells, such as monocytesmacrophages and dendritic cells, which is essential for the subsequent activation of antigen-specific adaptive immune responses. Stimulation of TLRs on antigen-presenting cells also induces the production of various cytokines that control the balance between T helper types 1 and 2 (Th1 and Th2) responses. For example, various TLR ligands lead to the production of interleukin (IL)-12, a key inducer of Th1 responses. The amount of IL-12 produced during stimulation is crucial for promoting the inflammatory responses to remove the invading microorganisms. Phosphoinositide 3-kinase (PI3K) is a lipid kinase that catalyzes the transfer of the g-phosphate group of ATP to the D3 position of phosphoinositides. Its product, PtdIns (3,4,5)P3 (PIP3), targets Akt/PKB, Bruton’s tyrosine kinase (Btk), PDK, atypical PKCs, phospholipase Cg and others. Numerous studies have implicated PI3K as a regulator of TLR signaling. However, there are conflicting reports concerning the physiological role of PI3K in the signaling pathway; the inconsistent results are partly due to the inadequate use of chemical inhibitors in these investigations. Although there is ample evidence indicating that various TLR ligands activate PI3K, it is yet not clear which subtype of PI3K is activated. It still needs to be determined how TLR stimulation activates the subtype. In this paper, these issues are reviewed so as to consolidate our current understanding of the role that PI3K plays in TLR signaling.