Expression of a Functional C5a Receptor in Regenerating Hepatocytes and Its Involvement in a Proliferative Signaling Pathway in Rat

Abstract

Activation of the complement system generates the anaphylatoxin C5a whose activities are mediated through its binding to the widely expressed C5aR. C5aR mRNA and protein expressions are known to be induced in rat hepatocytes under inflammatory conditions. However, little is known about the role of the C5a/C5aR complex in liver and its involvement during a proliferative process. We have evaluated the expression of C5aR in regenerating rat hepatocytes following a partial hepatectomy and in hepatocyte cultures. C5aR induction was observed in hepatocytes from regenerating liver, as well as in normal hepatocytes under a culture-induced stress. The effect of a stimulation by a C5a agonist upon the synthesis of a growth factor/receptor pair (hepatocyte growth factor/c-Met) was also evaluated. Our data demonstrated an up-regulated expression of hepatocyte growth factor and c-Met mRNAs, but we failed to observe a direct mitogenic effect of C5a in culture. However, a significantly increased expression of cyclin E and D1mRNA levels, as well as an increased BrdU incorporation, were observed in rats given an i.v. C5a agonist injection following an 80% partial hepatectomy. These studies demonstrate for the first time that: 1) C5aR is up-regulated during liver regeneration, 2) the binding of C5a to C5aR promotes a growth response, and 3) C5aR is involved in a cell cycle signaling pathway. Taken together, these findings point to a novel role for the hepatic C5aR implicating this complement system in the context of normal or abnormal proliferative pathways.

The Role of the Complement System and the Activation Fragment C5a in the Central Nervous System

“…The primary immune cells of the CNS, microglia and astrocytes, have been demonstrated to utilize components of the complement system, to provide the brain with immune sensors and response capabilities. In addition, recent findings provide evidence of a complement-mediated role in peripheral and nervous tissue development and regeneration (Daveau et al 2004;Mastellos et al 2005;Rahpeymai et al 2006;Stevens et al 2007;Benard et al 2008). Thus, a more modern view of the complement system has arisen which recognizes the role of complement in bridging the gap between the innate and adaptive immune responses as well as mediating tissue homeostasis.…”

Cancer and the Complement Cascade

“…This finding is especially interesting in light of the mitogenic properties of epidermal growth factor receptor activation (39). Finally, C5a/C5aR binding is known to induce cyclin E and D1 mRNA levels (40), phospholipase C β2 (41), phospholipase D (42), and Raf-1/B-Raf-mediated activation of MAPK/ERK kinase-1 (43), all demonstrable mediators of oncogenic transformation and progression. Intriguingly, two studies have shown direct complementmediated neoplastic proliferation.…”

“…In rats undergoing partial hepatectomy, C5a stimulation of injured liver cells results in increased mRNA expression of hepatocyte growth factor and its corresponding c-MET receptor (40). Both are known to possess potent mitogenic and anti-apoptotic effects in liver regeneration (66,67), and dysregulation of this pathway is strongly exhibited by many cancers (68).…”

A Novel Function of Thrombin-activatable Fibrinolysis Inhibitor during Rat Liver Regeneration and in Growth-promoted Hepatocytes in Primary Culture

“…In complement-deficient mice, the liver regeneration after partial hepatectomy or the liver restoration after CCl 4 -induced injury is markedly delayed (49). It is also known that C5 induces hepatocyte growth factor, cyclin E, or cyclin D1 expression via C5a receptors and stimulates hepatocyte proliferation (35). Taken together, the reduced expression of TAFI during liver regeneration might be favorable or even essential to the hepatocytes for their proliferation under the conditions thus provided.…”