Platelet-derived Growth Factor-BB and Thrombin Generate Positive and Negative Signals for Human Hepatic Stellate Cell Proliferation

Abstract

Proliferation of myofibroblastic hepatic stellate cells (HSC) in response to growth factors is essential for the development of liver fibrosis. We have reported that prostaglandins (PG) and cyclic AMP (cAMP) inhibit growth of human HSC. This PG/cAMP pathway transduces the endothelin (ET) B-mediated antiproliferative effect of endothelin-1 (ET-1) and up-regulates ETB receptors. Here, we show that platelet-derived growth factor (PDGF)-BB and thrombin, although mitogenic, generate growth inhibitory PGE 2 in myofibroblastic human HSC. The two peptides elicit early PGE 2 and cAMP synthesis, and also promote delayed induction of cyclooxygenase (COX)-2. Both early and delayed production of PGE 2 counteract the mitogenic effect of PDGF-BB and thrombin because: (i) pretreatment with the COX inhibitor ibuprofen markedly enhances the mitogenic effect of both peptides; (ii) blocking early synthesis of PGE 2 greatly enhances extracellular signal-regulated kinase (ERK) activation by both growth factors; (iii) enhancement of DNA synthesis by ibuprofen is only lost when the inhibitor is added after COX-2 induction has occurred. Finally, PDGF-BB and thrombin raise ETB receptors through the PG pathway. Thus, ibuprofen blunts growth factor-induced increase in ETB receptors. Up-regulation of the growth inhibitory ETB receptors by both mitogens may enhance the antiproliferative effect of ET-1 and thereby establish a negative feedback of their mitogenic effect. Our results shed light on novel growth inhibitory signals evoked by two mitogenic growth factors expressed during liver injury.

Nitrovasodilators inhibit platelet-derived growth factor-induced proliferation and migration of activated human hepatic stellate cells

“…As shown in Figure 8A, pretreatment with ibuprofen exerted a dose-related abrogation of the inhibitory effect of NO donors on PDGF-induced DNA synthesis. In addition, pretreatment with ibuprofen significantly enhanced the mitogenic effect of PDGF, similar to the data of Mallat et al 51 Accordingly, the observed inhibition of PDGF-induced ERK activity exerted by NTG and SNAP was completely abolished when cells were preincubated with ibuprofen ( Figure 8B). Finally, to characterize the involvement of the adenylate cyclase/ cAMP pathway, we examined intracellular cAMP synthesis in response to NO donors in the absence and presence of ibuprofen.…”

“…Along these lines, established experimental evidence obtained in activated human HSCs has clearly shown that activation of this signaling pathway is associated with effects on PDGF action and signaling similar to those observed in the presence of NO donors. [51][52][53] In agreement with this alternative working hypothesis, PGE 2 synthesis blockade obtained by using the COX inhibitor ibuprofen results in a decrease in NO donor-induced cAMP synthesis and in abrogation of the inhibitory effect of NO donors on both PDGF action and intracellular signaling.…”

“…In addition, a 2-fold increase in PGE 2 synthesis was also observed after stimulation with PDGF-BB, thus confirming recently reported observations in this cell type. 51 …”

Antiproliferative Properties of Sphingosine 1-Phosphate in Human Hepatic Myofibroblasts

“…Indeed, we found that the antiproliferative effects of ET-1 and TNF-␣ involve COX-2 (6). We also showed that the mitogenic effects of PDGF-BB and thrombin result from a balance between a promitogenic and a COX-2-dependent growth inhibitory pathway (5). Therefore, the present data further support a central role of COX-2 in hMF growth inhibition.…”

Insulin-like growth factor-I induces cyclooxygenase-2 expression via PI3K, MAPK and PKC signaling pathways in human ovarian cancer cells☆

“…IL-1β-induced COX-2 expression was enhanced by IGF-I treatment in rat renal mesangial cells (23). However, other recent studies showed that IGF-I failed to induce COX-2 expression in HT-29 colon cancer cells, hepatic stellate cells, and human vein vascular endothelial cells (13,24,25), and IGF-I treatment even decreased COX-2 expression in osteoblasts (26). Thus, the effects of IGF-I on COX-2 expression appear to be cell-type specific, which may reflect its ability to promote organ-specific tumorigenesis (2-4).…”