Hepatocyte proliferation following partial hepatectomy is an important component of liver regeneration, and recent in vitro studies have shown that IL-22 is involved in cellular proliferation in a variety of cell types, including hepatocytes. IL-22 functions through IL-10Rbeta and IL-22Ralpha. The goal of this study was to investigate the potential role of IL-22 in liver regeneration after 70% hepatectomy. Following 70% hepatectomy, done under general anesthesia in mice, serum IL-22 and hepatic IL-22Ralpha mRNA were significantly increased. Although administration of exogenous IL-22 prior to hepatectomy did not increase hepatocyte proliferation, administration of anti-IL-22 antibody before hepatectomy did significantly decrease hepatocyte proliferation. Furthermore, IL-22 treatment prior to 70% hepatectomy induced stat-3 activation; no significant changes were seen in ERK1/2 activation, stat-1 activation, or stat-5 activation. IL-22 pretreatment also significantly increased hepatic and serum IL-6 levels. In addition, animals treated with anti-IL-22 antibody also expressed less TGF-alpha. In conclusion, these data suggest that IL-22 is involved in liver regeneration and this may be due to interaction with IL-6 and TGF-alpha cascades.

Background and Purpose-Proven behavioral assessment strategies for testing potential therapeutic agents in rat stroke models are needed. Few studies include tasks that demand higher levels of sensorimotor and cognitive function. Because behavioral outcome and rate of recovery vary among ischemia models, there is a need to characterize and compare performance on specific tasks across models. Methods-To this end, sensorimotor and cognitive deficits were assessed during a 5-week period after either permanent proximal middle cerebral artery occlusion (pMCAO) or permanent distal middle cerebral artery occlusion combined with a 90-minute occlusion of both common carotid arteries (dMCAO/tCCAO) in Sprague-Dawley rats. The EBST, hindlimb and forelimb placing, and cylinder tests were given at regular intervals postinjury to assess sensorimotor function. Cognitive function was assessed with a multitrial water navigation task. Results-pMCAO, which caused both striatal and cortical damage, produced persistent sensorimotor and cognitive deficits. Limb placing responses and postural reflexes were impaired throughout the month of testing. A persistent bias for using the ipsilateral forelimb for wall movements in the cylinder test was observed as well as a bias for landing on the opposite forelimb. pMCAO rats were also impaired in the water navigation task. dMCAO/tCCAO, which caused only cortical damage, produced similar sensorimotor deficits, but these were greatly diminished by 2 weeks after injury.No impairment was found for water tank navigation. Correlations between forelimb placing (both models), water navigation performance (pMCAO model), and sensorimotor asymmetry (dMCAOtCCAO model) and infarct volume were observed. Conclusions-Based on the range of functions affected and stability of observed deficits, the pMCAO model appears to be preferable to the dMCAO/tCCAO model for use in assessing therapeutic agents for stroke.

Tumor-associated macrophages (TAMs) are major components of the tumor microenvironment. Although a role for TAMs in promoting tumor progression has been revealed, the differentiation mechanisms and intrinsic signals of TAMs regulated by the tumor microenvironment remain unclear. Here we constructed an in vitro TAMs cell model, TES-TAMs, which is from tumor-extract-stimulated bone-marrow-derived macrophages. We performed a comparative proteomics analysis of bone-marrow-derived macrophages and TES-TAMs, which indicated that TES-TAMs possessed characteristic molecular expression of TAMs. Intriguingly, the signal pathways enriched in up-regulated differentially expressed proteins of TAMs demonstrated that glycolysis metabolism reprogramming may play an important role in TAM differentiation. We found that hexokinase-2, a key mediator of aerobic glycolysis, and the downstream proteins PFKL and ENO1 were remarkably increased in both TES-TAMs and primary TAMs from our MMTV-PyMT mice model. This phenomenon was then verified in human THP-1 cell lines stimulated by tumor extract solution from breast cancer patient. Taken together, our study provides insight into the induction of TAM differentiation by the tumor microenvironment through metabolic reprogramming.

Partial hepatectomy triggers hepatocyte proliferation, hepatic matrix remodeling, and hepatocyte apoptosis, all of which are important processes in the regenerating liver. Previous studies have shown an increase in the levels of matrix metalloproteinases gelatinase A (MMP-2) and gelatinase B (MMP-9) after partial hepatectomy. The goal of this study was to investigate the role of MMP-9 in liver regeneration after partial hepatectomy. A 70% hepatectomy or sham laparotomy was performed in wild-type or MMP-9 -deficient (MMP-9 ؊/؊ ) mice. Hepatic regeneration was determined by liver weight/total body weight ratios and BrdU staining, which was used to a calculate mitotic index at several times postoperatively. Cytokine and growth factor expression was evaluated by Luminex™ bead-based ELISA and Western blots. Finally, the effect of MMP-9 on apoptosis was measured using TUNEL and caspase expression. The MMP-9 ؊/؊ animals had a delayed hepatic regenerative response when compared with wild-type controls. The MMP-9 -deficient animals expressed significantly less VEGF, HGF, and TNF-␣ between days 2 and 3 post-hepatectomy. Apoptosis, as measured by TUNEL staining and caspase expression, was decreased in the MMP-9 ؊/؊ . In conclusion, MMP-9 plays an important role in liver regeneration after partial hepatectomy by affecting matrix remodeling, as well as cytokine, growth factor, and caspase expression.

Recent studies show CXC chemokine elevations after hepatic resection; blockade of epithelial neutrophilactivating protein (ENA-78), a CXC chemokine, retards hepatic regeneration after resection. Additional studies demonstrate that exogenous macrophage inflammatory protein (MIP)-2, another CXC chemokine, is therapeutic in a murine acetaminophen toxicity model when other therapies fail. The current investigations study MIP-2's effects on the cellular mechanisms involved in liver regeneration in mice after 70% hepatectomy. Administration of exogenous MIP-2 after 70% hepatectomy dramatically increased hepatocyte proliferation as measured by 5-bromo-2-deoxyuridine staining. Signal transducer and activator of transcription-3 (stat-3) was also detected in greater abundance and persisted in hepatic nuclear extracts from MIP-2-treated mice compared with control mice after hepatic resection. Further, inhibition of the MIP-2 receptor, CXCR2, decreased baseline hepatocyte proliferation and stat-3 expression in the setting of partial hepatectomy. These data show that MIP-2 is important for hepatocyte proliferation after partial hepatectomy and that pharmacological MIP-2 doses after hepatic injury accelerate hepatic regeneration. The liver is the only vital organ, aside from the brain, for which we have no pharmacological, mechanical, or extra corporeal means of support for a failing organ. In contrast, we have mechanical ventilation to support patients with pulmonary failure, dialysis to support failing kidneys, and a variety of mechanical and pharmacological interventions to maintain the failing heart. The liver is also unique in that it is the only mammalian organ that can regenerate its biologically functional parenchymal mass after resection or injury, instead of healing with biologically nonfunctional scar. A patient's ability to restore his or her preoperative hepatic mass after major liver resection is well known.1 A multitude of mediators that are hepatic mitogens, both in vitro and in vivo, have been identified, but the precise mechanisms involved in liver regeneration remain to be defined. 2In the quest to elucidate the mechanisms responsible for this unique feature of the liver, extensive studies have been conducted in various clinically relevant models of hepatic injury, including partial hepatectomy, ischemiareperfusion injury, pathogenic infection, and drug toxicity. Novel treatments for liver injury because of hepatic resection may stem from recent studies demonstrating that cytokines, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-␣, and CXC chemokines, such as IL-8, epithelial neutrophil activating protein (ENA-78), and macrophage inflammatory protein-2 (MIP-2), are important priming factors for hepatocyte proliferation and hepatic regeneration. [3][4][5] It is now well established that TNF and IL-6, important inflammatory cytokines, have mitogenic effects on the liver.3,6 -8 Recent studies illustrate that at least some of TNF's proliferative effects are mediated via TNF-induced IL-6 up-regulatio...