Abstract
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine implicated in the pathogenesis of inflammation and cancer. It is produced by various cells and circulating MIF has been identified as a biomarker for a range of diseases. Extracellular MIF mainly binds to the cluster of differentiation 74 (CD74)/CD44 to activate downstream signaling pathways. These in turn activate immune responses, enhance inflammation and can promote cancer cell proliferation and invasion. Extracellular MIF also binds to the C-X-C chemokine receptors cooperating with or without CD74 to activate chemokine response. Intracellular MIF is involved in Toll-like receptor and inflammasome-mediated inflammatory response. Pharmacological inhibition of MIF has been shown to hold great promise in treating inflammatory diseases and cancer, including small molecule MIF inhibitors targeting the tautomerase active site of MIF and antibodies that neutralize MIF. In the current review, we discuss the role of MIF signaling pathways in inflammation and cancer and summarize the recent advances of the role of MIF in experimental and clinical exocrine pancreatic diseases. We expect to provide insights into clinical translation of MIF antagonism as a strategy for treating acute pancreatitis and pancreatic cancer.
Highlights
Macrophage migration inhibitory factor (MIF) was originally discovered in 1966 as a lymphokine derived from activated T cells during delayed-type hypersensitivity (Bloom and Bennett, 1966; David, 1966), exhibiting inhibition function of macrophage migration
As for CER-Acute pancreatitis (AP) in rats, the MIF levels were only markedly elevated in pancreatic ascites and peritoneal macrophages were considered to be the cellular sources of ascitic MIF
The MIF levels in pancreatic tissue and serum were increased in L-arginine-induced AP (ARG-AP) in mice (Ohkawara et al, 2017) and their expression was up-regulated in the intrahepatic bile duct cells in a sodium taurocholateinduced AP (STC-AP) in rats (Wang et al, 2019)
Summary
Macrophage migration inhibitory factor (MIF) was originally discovered in 1966 as a lymphokine derived from activated T cells during delayed-type hypersensitivity (Bloom and Bennett, 1966; David, 1966), exhibiting inhibition function of macrophage migration. Acute pancreatitis (AP) is one of the most common gastroenterological diseases with an increasing global incidence and is complicated by considerable comorbidity, mortality, and financial burden (Peery et al, 2019; Petrov and Yadav, 2019). In the course of the disease, injured pancreatic acinar cells secrete inflammatory mediators such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), MIF, chemokines and their ligands that mediate recruitment and infiltration of neutrophils and monocytes at the injury site (Lugea et al, 2017), further aggravating local injury and systemic inflammation (Linkermann et al, 2014). The current treatment of AP is limited to supportive care as well as the management of local and systemic complications (Vege et al, 2018)
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