Cell migration is a fundamental biological process involving membrane polarization and cytoskeletal dynamics, both of which are regulated by Rho family GTPases. Among these molecules, Rac is crucial for generating the actin-rich lamellipodial protrusion, a principal part of the driving force for movement. The CDM family proteins, Caenorhabditis elegans CED-5, human DOCK180 and Drosophila melanogaster Myoblast City (MBC), are implicated to mediate membrane extension by functioning upstream of Rac. Although genetic analysis has shown that CED-5 and Myoblast City are crucial for migration of particular types of cells, physiological relevance of the CDM family proteins in mammals remains unknown. Here we show that DOCK2, a haematopoietic cell-specific CDM family protein, is indispensable for lymphocyte chemotaxis. DOCK2-deficient mice (DOCK2-/-) exhibited migration defects of T and B lymphocytes, but not of monocytes, in response to chemokines, resulting in several abnormalities including T lymphocytopenia, atrophy of lymphoid follicles and loss of marginal-zone B cells. In DOCK2-/- lymphocytes, chemokine-induced Rac activation and actin polymerization were almost totally abolished. Thus, in lymphocyte migration DOCK2 functions as a central regulator that mediates cytoskeletal reorganization through Rac activation.

Camostat mesilate (CM), an oral protease inhibitor, has been used clinically for the treatment of chronic pancreatitis in Japan. However, the mechanism by which it operates has not been fully understood. Our aim was to evaluate the therapeutic efficacy of CM in the experimental pancreatic fibrosis model induced by dibutyltin dichloride (DBTC), and we also determined the effect of CM on isolated monocytes and panceatic stellate cells (PSCs). In vivo, chronic pancreatitis was induced in male Lewis rats by single administration of 7 mg/kg DBTC and a special diet containing 1 mg/g CM was fed to the DBTC þ CM-treated group from day 7, while the DBTC-treated group rats were fed a standard diet. At days 0, 7, 14 and 28, the severity of pancreatitis and fibrosis was examined histologically and enzymologically in both groups. In vitro, monocytes were isolated from the spleen of a Lewis rat, and activated with lipopolysaccharide stimulation. Thereafter, the effect of CM on monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-a (TNF-a) production from monocytes was examined. Subsequently, cultured rat PSCs were exposed to CM and tested to see whether their proliferation, MCP-1 production and procollagen a1 messenger RNA expression was influenced by CM. In vivo, the oral administration of CM inhibited inflammation, cytokines expression and fibrosis in the pancreas. The in vitro study revealed that CM inhibited both MCP-1 and TNF-a production from monocytes, and proliferation and MCP-1 production from PSCs. However, procollagen a1 expression in PSCs was not influenced by CM. These results suggest that CM attenuated DBTC-induced rat pancreatic fibrosis via inhibition of monocytes and PSCs activity.

Retroperitoneal fibrosis is a rare disease characterized by the development of inflammation and fibrosis in the soft tissues of the retroperitoneum and other abdominal organs. Retroperitoneal fibrosis can be of 2 types: idiopathic and secondary. The recently advocated concept and diagnostic criteria of immunoglobulin G4 (IgG4)-related disease, derived from research on autoimmune pancreatitis (AIP), has led to widespread recognition of retroperitoneal fibrosis as a condition caused by IgG4-related disease. We now know that previously diagnosed idiopathic retroperitoneal fibrosis includes IgG4-related disease; however, the actual prevalence is unclear. Conversely, some reports on AIP suggest that retroperitoneal fibrosis is concurrently found in about 10% of IgG4-related disease. Because retroperitoneal fibrosis has no specific symptoms, diagnosis is primarily based on diagnostic imaging (computed tomography and magnetic resonance imaging), which is also useful in evaluating the effect of therapy. Idiopathic retroperitoneal fibrosis can occur at different times with other lesions of IgG4-related disease including AIP. Thus, the IgG4 assay is recommended to diagnose idiopathic retroperitoneal fibrosis. High serum IgG4 levels should be treated and monitored as a symptom of IgG4-related disease. The first line of treatment for retroperitoneal fibrosis is steroid therapy regardless of its cause. For patients with concurrent AIP, i.e., IgG4-related retroperitoneal fibrosis, the starting dose of steroid is usually 30-40 mg/d. The response to steroid therapy is generally favorable. In most cases, the pancreatic lesion and retroperitoneal fibrosis improve after the initial treatment. However, the epidemiology, treatment for recurring retroperitoneal fibrosis, and long-term prognosis are still largely unknown. Further analysis of such cases and research are necessary.

Background: Monocyte chemoattractant protein 1 (MCP-1) is a member of the C-C chemokine family and exerts strong chemoattractant activity in monocytes, macrophages, and lymphocytes. Rat pancreatic fibrosis induced by dibutyltin dichloride (DBTC) is considered to be an appropriate chronic pancreatitis model histologically and enzymatically, as has demonstrated in a previous study. Aim: We examined the effect of human dominant negative inhibitor of MCP-1 (mutant MCP-1) on progression of chronic pancreatitis induced by DBTC in a rat model. Methods: We used the experimental model of chronic pancreatitis induced by DBTC in rats. Mutant MCP-1 or empty plasmid at a dose of 50 mg/body weight was administrated into rat thigh muscles on days 4, 11, and 18 after administration of DBTC. On days 14 and 28, we evaluated the effect of mutant MCP-1 morphologically and biochemically. Results: The mutant MCP-1 treated group inhibited early pancreatic inflammation and later pancreatic fibrosis histologically, and showed a decrease in serum MCP-1 concentration, intrapancreatic hydroxyproline, a-smooth muscle actin, and an increase in intrapancreatic amylase and protein content compared with the empty plasmid treated group. The mutant MCP-1 group also inhibited intrapancreatic mRNA expression of cytokines and chemokines. Conclusions : Our findings suggest that monocyte/macrophage recruitment and the systemic MCP-1 signal pathway contribute to progression of chronic pancreatitis, and that blockade of MCP-1 may suppress the development of pancreatic fibrosis.

MCP-1 appears to be involved in the progression of severe forms of acute pancreatitis. Our data suggested that MCP-1 is a candidate as a therapeutic target to treat acute pancreatitis.