Richard J. Bucala

MIF Family Cytokines in Innate Immunity and Homeostasis

Macrophage migration inhibitory factor (MIF) is a pluripotent cytokine/ chemokine that is an important component of the innate immune response. Recent studies have identified multiple roles for MIF in the progression and resolution of different stages of inflammatory and fibrotic response to liver injury. Here we review the basic functions of MIF and its cognate and non-cognate receptors in hepatic injury and repair, with an emphasis on alcoholic and nonalcoholic liver disease. Specific functions of MIF and its receptors in hepatocytes, Kupffer cells (the resident macrophage in the liver), and hepatic stellate cells are discussed in the context of hepatocyte injury, inflammatory responses and fibrogenesis. Finally, we analyze the potential for MIF as a therapeutic target for hepatic inflammatory and fibrotic diseases. 1 Overview of MIF Pathway Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory mediator. MIF was the first discovered active cytokine [1], but the protein was not cloned and characterized until the 1990s [2]. MIF was initially found to inhibit the random migration of macrophages and was associated with macrophage phagocytosis. MIF is constitutively expressed in both immune and nonimmune cells including various peripheral tissues, and its tissue distribution is almost ubiquitous. Besides its effect on monocyte/macrophage mobility, MIF is also known to be an upstream regulator of immunity and has a chemokine-like function, promoting the directed migration and recruitment of leukocytes into infectious and inflammatory sites [3] (Fig. 1). Its most critical functions encompass the regulation of macrophage function [4, 5], lymphocyte immunity [6, 7], and endocrine functions [7–9]. In contrast to other pro-inflammatory cytokines that are generally suppressed by glucocorticoids, MIF is a unique counter regulator of the immunosuppressive and Fig. 1 Mode of action of MIF. (a) Interactions of MIF with its receptors and activation of signaling pathways. MIF binds a multicomponent receptor comprising two transmembrane proteins: the CD74 ligand-binding protein and the CD44 signal transducer. The MIF-CD74-CD44 complex formation activates Src-family protein tyrosine kinase and ERK1/2-MAPK, ultimately leading to the regulation of transcription factors controlling gene expression involved in cell cycle control, cellular proliferation and cell death, as well as expression of chemokines. MIF activation of CD74/CD44 also activates c-jun N-terminal kinase/stress-activated protein kinase (pJNK) increasing the posttranscriptional stability of mRNAs for pro-inflammatory cytokines such as TNF. MIF also induces signal transduction by binding to CXCR2 and CXCR4, triggering cytosolic Ca2+ influx, integrin activation, and GTPase activation via Gαi, resulting in cell adhesion, migration and proliferation. MIF binds directly to the CXCR7 inducing downstream activation of PI3K-Akt and the phosphorylation-mediated inactivation of pro-apoptotic protein BAD exerts anti-apoptotic effects. (b) MIF counter-regulation of glucocorticoids. Glucocorticoids inhibit NF-κB activation, in part, by increasing the expression of IκBα. Glucocorticoids also mediate mRNA destabilization. MIF inhibits IκBinduced synthesis, counteracts inhibition of NF-κB and stabilizes mRNA. Glucocorticoids inhibition of PLA2 activity and arachidonic acid production is also blocked by MIF V. Marin et al.

Identification of a minimal peptide sequence of islet amyloid polypeptide (IAPP) with amyloidogenic and cytotoxic properties

Aphrodite Kapurniotu, Jurgen Bernhagen, Wolfgang Fischle, Saul Teichberg, Wolfgang Voelter and Richard Bucala Physiologisch-chemisches Institut, Hoppe-Seylerstr. 4, D-72076 Tubingen, Germany; Universitat Stuttgart, Fraunhofer Institut, Nobelstr. 12, D-70569 Stuttgart, Germany; North Shore University Hospital, 300 Community Drive, Manhasset, NY 11030, USA; The Picower Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA