Figure 7

Signaling pathways involved in LPS induced TNFalpha production in human adipocytes. LPS, with LBP and CD14 (coming from medium) bind to TLR4 on mature human adipose cells. Binding activates two main pathways in the cells. One pathway leads to the activation of NFkappaB (through TRAF6 and IKK). The other pathway passes through phosphorylated p38 MAP Kinase. Both pathways enable the activation of TNFalpha transcription, followed by cleavage of the protein via a membrane metalloprotease, ADAM17 or TACE, leading to the release of the soluble form of TNFalpha. The PI3K represents a third pathway, which activates NFkappaB and p38 MAPK. Another kinase, maybe the PI4K, plays an inhibitory role in the LPS activation of these 2 pathways. As far as the PKC is concerned, it probably activates IKK, or the p38 MAPKs, or both pathways. However, activation is only visible once the PI4K is inactive. It is therefore possible that PI4K constitutively inhibits PKC.