Increased Serum Enzyme Levels Associated with Kupffer Cell Reduction with No Signs of Hepatic or Skeletal Muscle Injury

Abstract

Macrophage colony-stimulating factor (M-CSF) is a hematopoietic growth factor that is responsible for the survival and proliferation of monocytes and the differentiation of monocytes into macrophages, including Kupffer cells (KCs) in the liver. KCs play an important role in the clearance of several serum enzymes, including aspartate aminotransferase and creatine kinase, that are typically elevated as a result of liver or skeletal muscle injury. We used three distinct animal models to investigate the hypothesis that increases in the levels of serum enzymes can be the result of decreases in KCs in the apparent absence of hepatic or skeletal muscle injury. Specifically, neutralizing M-CSF activity via a novel human monoclonal antibody reduced the CD14 ؉ CD16 ؉ monocyte population, depleted KCs, and increased aspartate aminotransferase and creatine kinase serum enzyme levels in cynomolgus macaques. In addition, the treatment of rats with clodronate liposomes depleted KCs and led to increased serum enzyme levels, again without evidence of tissue injury. Finally, in the osteopetrotic (Csf1 op /Csf1 op ) mice lacking functional M-CSF and having reduced levels of KCs, the levels of serum enzymes are higher than in wild-type littermates. Together, these findings support a mechanism for increases in serum enzyme levels through M-CSF regulation of tissue macrophage homeostasis without concomitant histopathological changes in either the hepatic or skeletal system.

Depletion of Hepatic Macrophages Aggravates Liver Lesions Induced in Rats by Thioacetamide (TAA)

“…Therefore, coagulation necrosis of hepatocytes seen in TAA þ CLD group should be caused by toxic effects of TAA itself but not by macrophage-produced cytotoxic factors. The findings that the values of hepatic enzymes such as AST, ALT, and ALP on days 2 and 3 were greater in the TAA þ CLD group might have been due mainly to aggravated hepatocyte damage or partly to decreased clearance of hepatic enzymes by macrophages (Smit et al 1987;Radi et al 2011). The action of M1 macrophages is regulated by M2 macrophages, which are primarily involved in downregulating inflammation and initiating reparative fibrosis (Martinez et al, 2008;Laskin et al 2011;Sindrilaru and Scharffetter-Kochanek 2013).…”

“…Increased value of ALP and decreased mRNA level of IL-10 on day 0 might be related to the depleted Kupffer cells in TAA þ CLD group, indicating the roles of Kupffer cells on liver homeostasis via clearance or production of such factors (Smit et al 1987;Radi et al 2011). …”

Results from a Phase IIA Parallel Group Study of JNJ-40346527, an Oral CSF-1R Inhibitor, in Patients with Active Rheumatoid Arthritis despite Disease-modifying Antirheumatic Drug Therapy

“…The mean increases in liver function enzymes, including creatine kinase, LDH, AST, and ALT, observed more commonly in JNJ-40346527-treated than placebo-treated patients, are expected given that the active agent can potentially inhibit Kupffer cell activity in the liver that serves to clear these enzymes 15 . Similar side effects have been observed in healthy subjects receiving a monoclonal antibody directed against CSF-1 (PD-0360324) 14 .…”

Anti-climacterium effects of pomegranate concentrated solutions in ovariectomized ddY mice

“…These findings supported the favorable hepatoprotective activity of PCS. Since the liver is the main target organ of HMG-CoA reductase (45,72), hypertrophy and fatty change in hepatocytes are accompanied by increased AST and ALT activities (73,74), which are related to estrogen deficiency-mediated obese and hyperlipidemia (45,74,75). Estrogen deficiency is associated with an atherogenic lipid profile characterized by HDL-cholesterol, LDL-cholesterol, triglyceride levels (11), central adiposity (12), increased diastolic pressure (13), and increased insulin resistance (14).…”