Novel Function of Prostaglandins as Inducers of Gene Expression of HGF and Putative Mediators of Tissue Regeneration

Abstract

Prostaglandins (PGs) are multi-potent mediators for local tissue homeostasis and inflammatory reactions. Addition of PGs to cultures of human skin fibroblasts led to a marked induction of the production of hepatocyte growth factor (HGF). PGE1 and PGI2 analogues were the most potent in stimulating HGF production by over 50-fold; PGE2 and PGD2 were less potent. Western immunoblotting of conditioned medium from skin fibroblasts indicated that both PGE1, PGE2, and PGI2 analogues specifically induce synthesis of HGF with a M(r) of 85,000, but not smaller variant of HGF with a M(r) of 28,000. Consistent with the induction of HGF production, steady-state expression of HGF mRNA in fibroblasts was strongly induced by PGE1 and PGI2 analogues, but slightly by PGE2 and PGD2, thereby indicating that PGs induce HGF production through transcriptional activation of the HGF gene. PGE1, PGE2, PGI2 analogue also stimulated HGF production in MRC-5 human embryonic lung fibroblasts and vascular smooth muscle cells. As dibutyryl cyclicAMP (dbcAMP) and tetradecanoylphorbol 13-acetate (TPA), but not Ca(2+)-ionophore A23187 stimulated HGF production in skin fibroblasts, activation of protein kinase-A and protein kinase-C may be coupled to the stimulation of HGF production. Simultaneous addition of PGE1 and TPA or dbcAMP and TPA led to a synergistic enhancement of HGF production, whereas the simultaneous addition of PGE1 and dbcAMP failed to additively enhance HGF production.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatocyte growth factor and the Met system as a mediator of tumor–stromal interactions

“…1,[34][35][36][37][38] In this context, it is noteworthy that prostaglandins (e.g., PGE1, PGE2 and PGI2), synthesized by the cyclooxygenase-2 (COX-2)-mediated metabolic pathways, are among the most potent inducers of the gene expression of HGF in fibroblasts. 39 Interestingly, while COX-2 is often expressed in cancer cells in the human colon and other organs, its expression in precancerous benign polyps is found in stromal fibroblasts and endothelial cells but not in mucosal epithelial cells in both human familial adenomatous polyposis and the mouse model Apc mutants. 40 Likewise, IL-1 stimulates HGF expression through the induction of COX-2 in fibroblasts (our unpublished data).…”

Suppression of fibrogenic gene expression and liver fibrosis using a synthetic prostacyclin agonist

“…The gene expression of HGF is transcriptionally regulated by different types of extracellular signaling molecules, including interleukin-1, chemokines, growth factors, and prostaglandins (PGE 1 /E 2 and PGI 2 ) (6,15,22,26,33). Prostaglandin receptors are G-protein-coupled receptors that evoke different effectors and signaling pathways.…”

Biphasic regulation by bile acids of dermal fibroblast proliferation through regulation of cAMP production and COX-2 expression level

“…We hypothesize that an increased deposition of bile acids not only in the liver but also in the skin could lead to tissue injury and the alteration of the balance between cell proliferation and cell death induced by various hormones, cytokines, and growth factors. In addition, PGE1 has been suggested to play an important role in tissue regeneration, due to its ability to regulate hepatocyte growth factor expression in human dermal fibroblasts in a cAMP-dependent fashion (31). Finally, PGE1 has been shown to inhibit collagenase gene expression in human skin fibroblasts (14).…”