Tissue inhibitor of metalloproteinases‐2 (TIMP‐2) in rat liver cells is increased by lipopolysaccharide and prostaglandin E₂

Abstract

To explore the functional role of TIMP-2 in liver, we determined TIMP-2 mRNA levels in primary rat hepatocytes and in total rat liver. Rat hepatocytes constitutively express TIMP-2 mRNA at a low level. Incubation with dexamethasone, prostaglandin E2 and a combination of inflammatory cytokines leads to an up-regulation of TIMP-2 mRNA. In rats in vivo we found a dramatic increase of TIMP-2 expression after intraperitoneal injection of lipopolysaccharide. Compared to our previous findings on TIMP-1 we conclude that TIMP-2 mRNA expression is regulated in a distinct and partially opposite manner. Over-production of TIMP-2 could inhibit the activity of metalloproteinases and thus lead to matrix accumulation. Dysregulation of TIMP-2 synthesis might be involved in the development of liver fibrosis.

Expression of MMPs and TIMPs in liver fibrosis – a systematic review with special emphasis on anti-fibrotic strategies

“…Without any sign of fibrosis TIMP-2 elevation was presumably inflammation-or virus-related. In animal models of acute toxic liver injury rat TIMP-2 mRNA peaked transiently 2-3 days after a single injection of CCl 4 [48] or LPS [60]. Consistently, in chronic toxic liver injury no significant increase was observed in rats during an 8-week CCl 4 -challenge [29].…”

“…Initial evidence regarding the relatedness of TIMP-1 and TIMP-2, and hepatic fibrosis relies on findings in rat hepatocytes: in this setting treatment with inflammatory cytokines stimulated the transcription of both genes [58][59][60]. Later, enhanced expression of TIMP-1 and TIMP-2 was shown in two rat models of liver injury, provoked via CCl 4 injection and bile duct ligation [61].…”

Cyclooxygenase-2 Unlike Cyclooxygenase-1 is Highly Expressed in Ovine Embryos during the Implantation Period1

“…In ovine trophoblast, Cox-2 expression and the associated prostaglandin production could be the way in which the cells control the invasion of the trophoblast. It was effectively reported that cyclooxygenase end-products suppressed the production of metalloproteinases [52,53] and enhanced the expression of their inhibitors [54][55][56]. However, in other models, prostaglandins were also found to promote the synthesis of proteolytic enzymes [57][58][59].…”

Recombinant HBsAg inhibits LPS-induced COX-2 expression and IL-18 production by interfering with the NFκB pathway in a human monocytic cell line, THP-1

“…PGE2 plays an important role in liver pathogenesis. For example, PGE2 delays collagen formation and up-regulates tissue inhibitor of metalloproteinases-2 leading to matrix accumulation in rat liver [21]. It has been shown that plasma levels of PGE2 increase with the advancement of liver cirrhosis [22].…”