Unconjugated
BACKGROUND:
The role of cannabinoid receptor type 2 (Cnr2) in regulating immune function had been widely investigated, but the mechanism is not fully understood.
RESULTS:
Cnr2 activation down-regulates 5-lipoxygenase (Alox5) expression by suppressing the JNK/c-Jun activation.
CONCLUSION:
The Cnr2-JNK-Alox5 axis modulates leukocyte inflammatory migration.
SIGNIFICANCE:
Linking two important regulators in leukocyte inflammatory migration and providing a potential therapeutic strategy for treating human inflammation-associated diseases. Inflammatory migration of immune cells is involved in many human diseases. Identification of molecular pathways and modulators controlling inflammatory migration could lead to therapeutic strategies for treating human inflammation-associated diseases. The role of cannabinoid receptor type 2 (Cnr2) in regulating immune function had been widely investigated, but the mechanism is not fully understood. Through a chemical genetic screen using a zebrafish model for leukocyte migration, we found that both an agonist of the Cnr2 and inhibitor of the 5-lipoxygenase (Alox5, encoded by alox5) inhibit leukocyte migration in response to acute injury. These agents have a similar effect on migration of human myeloid cells. Consistent with these results, we found that inactivation of Cnr2 by zinc finger nuclease-mediated mutagenesis enhances leukocyte migration, while inactivation of Alox5 blocks leukocyte migration. Further investigation indicates that there is a signaling link between Cnr2 and Alox5 and that alox5 is a target of c-Jun. Cnr2 activation down-regulates alox5 expression by suppressing the JNK/c-Jun activation. These studies demonstrate that Cnr2, JNK, and Alox5 constitute a pathway regulating leukocyte migration. The cooperative effect between the Cnr2 agonist and Alox5 inhibitor also provides a potential therapeutic strategy for treating human inflammation-associated diseases.
Clonorchis sinensis is a high-risk pathogenic helminth that strongly provokes inflammation, epithelial hyperplasia, periductal fibrosis, and even cholangiocarcinoma in chronically infected individuals. Chronic inflammation is associated with an increased risk of various cancers due to the disruption of redox homeostasis. Accordingly, the present study was conducted to examine the time course relationship between histopathological changes and the appearance of oxidative stress markers, including lipid peroxidation, enzymes involved in lipid peroxidation, and mutagenic DNA adducts in the livers of mice infected with C. sinensis, as well as proinflammatory cytokines in infected mouse sera. Histopathological phenotypes such as bile duct epithelial hyperplasia, periductal fibrosis, edema and inflammatory infiltration increased in infected livers in a time-dependent manner. Intense immunoreactivity of lipid peroxidation products (4-hydroxy-2-nonenal; malondialdehyde), cyclooxygenase-2, 5-lipoxygenase and 8-oxo-7,8-dihydro-2'-deoxyguanosine were concomitantly observed in these injured regions. We also found elevated expressions of cyclooxygenase-2 and 5-lipoxygenase in C. sinensis excretory-secretory product-treated cholangiocarcinoma cells. Moreover, the levels of proinflammatory cytokines such as TNF-α, ILβ-1 and IL-6 were differentially upregulated in infected sera. With regard to oxidative stress-mediated carcinogenesis, our findings suggest that C. sinensis infestation may disrupt host redox homeostasis, creating a damaging environment that favors the development of advanced hepatobiliary diseases such as clonorchiasis-associated cholangiocarcinoma.
