Figure 9.

Possible mechanism of PIP-18 suppression on IL-stimulated expression of sPLA₂ and MMPs. IL-1β and/or TNF initiate the expression of secretory phospholipase A₂ (sPLA₂)-IIA and matrix metalloproteinases (MMP) through activation of mitogen-activated protein kinase (MAPK) cascade. (1) phospholipase inhibitor from python (PIP)-18 blocks p38 MAPK phosphorylation and reduces activation of transcription factors (activator protein-1 (AP-1), activating transcription factor 2 (ATF-2)), which regulate the transcription of sPLA₂-IIA, MMPs (MMP-1, MMP-2, MMP-3, MMP-9) and proinflammatory cytokines (IL-6, TNF, IL-1). This results in downregulation of these genes and decreased protein secretions. (2) Inhibition of sPLA₂ enzymatic activity by PIP-18 contributes to reduced generation of arachidonic acid for prostaglandin production. MAPKKK = MAPK kinase kinase; MAPKK = MAPK kinase; PGE2 = prostaglandin E2; sPLA₂-IIA = secretory phospholipase A₂-Group IIA; solid arrows, known pathways; ┤, inhibition (NF-κB pathway is not shown here).