Table Of ContentProgress in Infl ammation Research
Series Editors: Michael J. Parnham · Achim Schmidtko
Richard Bucala
Jürgen Bernhagen Editors
MIF Family
Cytokines in
Innate Immunity
and Homeostasis
Progress in Inflammation Research
Series Editors
Michael J. Parnham
Fraunhofer IME & Goethe University
Frankfurt, Germany
Achim Schmidtko
Goethe University
Frankfurt, Germany
More information about this series at http://www.springer.com/series/4983
Richard Bucala • Jürgen Bernhagen
Editors
MIF Family Cytokines in
Innate Immunity and
Homeostasis
Editors
Richard Bucala Jürgen Bernhagen
The Anlyan Center Department of Vascular Biology
Yale School of Medicine Institute for Stroke and Dementia Research
Yale University Ludwig-Maximilians-University (LMU)
New Haven, CT Munich
USA Germany
Series Editors
Michael J. Parnham Achim Schmidtko
Fraunhofer IME & Goethe University Goethe University
Frankfurt Frankfurt
Germany Germany
Progress in Inflammation Research
ISBN 978-3-319-52352-1 ISBN 978-3-319-52354-5 (eBook)
DOI 10.1007/978-3-319-52354-5
Library of Congress Control Number: 2017943027
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The Editors, Profs. Bucala and Bernhagen,
dedicate this volume to their spouses, Anne
and Aphrodite, with thanks for their long-
standing support to their scientific work
on MIF.
Contents
MIF- and CD74-Dependent Mechanisms ........................... 1
Shirly Becker-Herman, Naama Gil, Lihi Radomir, and Idit Shachar
HSP90-Stabilized MIF in Oncogenesis and Cell Growth Control ....... 21
Ramona Schulz-Heddergott and Ute M. Moll
CD74, MIF and Breast Tumorigenesis: Insights from Recent
Large-Scale Tumour Genomics and Proteomics Studies ............... 43
Metodi V. Metodiev
MIF-Dependent Regulation of Monocyte/Macrophage Polarization ..... 59
Kavitha Yaddanapudi and Robert A. Mitchell
Advances in Understanding the Role of MIF in the Pathogenesis
of Autoimmune Diseases ......................................... 77
Saisha A. Nalawade, Yousef Al-Abed, and Thomas G. Forsthuber
Role of MIF in Experimental Autoimmune Encephalomyelitis
and Multiple Sclerosis ........................................... 97
Gil Benedek, Roberto Meza-Romero, and Arthur A. Vandenbark
Role of MIF in Hepatic Inflammatory Diseases and Fibrosis ........... 109
Veronica Marin, Gemma Odena, Kyle Poulsen, Claudio Tiribelli,
Stefano Bellentani, Andrea Barchetti, Pau Sancho Bru, Natalia Rosso,
Ramon Bataller, and Laura E. Nagy
MIF and Pulmonary Disease ..................................... 135
Timothy Baker, Patty J. Lee, and Maor Sauler
MIF Mediates Pelvic Inflammation and Pain ....................... 145
Fei Ma, Katherine L. Meyer-Siegler, Karin N. Westlund,
and Pedro L. Vera
MIF Family Proteins in Cardiac Ischemia/Reperfusion Injury ......... 157
Christian Stoppe and Jürgen Bernhagen
viii Contents
The MIF-CD74 Inflammatory Axis in Alphaviral Infection ............ 175
Lara J. Herrero, Ali Zaid, Margit Mutso, and Suresh Mahalingam
MIF in Eosinophilic Inflammation ................................ 189
Marcelo T. Bozza, Claudia N. Paiva, and Priscilla C. Olsen
The Role of MIF in Parasitic Infections ............................ 203
Cesar Terrazas, James C. Stock, Jeniffer Kimble, Ellen Moretti,
Sanjay Varikuti, and Abhay R. Satoskar
Parasite MIF Orthologs ......................................... 221
Thomas Holowka and Richard Bucala
Index ......................................................... 241
MIF- and CD74-Dependent Mechanisms
Shirly Becker-Herman, Naama Gil, Lihi Radomir, and Idit Shachar
Abstract CD74 is a type II cell surface protein that was previously shown to play
a role in antigen presentation and as a receptor for the cytokine macrophage migra-
tion inhibitory factor (MIF). Studies from recent years demonstrate an important
role for CD74 in maintenance of innate and adaptive immune cells. This chapter
discusses the MIF/CD74-dependent role in regulating cell survival, metabolism,
adhesion, and response to hypoxia in health and disease.
1 CD74
The CD74 gene is located on human chromosome 5 (q32), and was first identified
in 1979 by Jones et al. [1]. However, it was not until 1989 that CD74 was shown to
have a role in antigen presentation [2]. CD74 is a non-polymorphic type II integral
membrane protein (thus also called invariant chain), which exists in different iso-
forms defined by its primary amino acid sequence. There are four isoforms of
CD74 in humans: p33, p35, p41, and p43. CD74 p33 and p41 are distinguished by
alternative splicing of the CD74 transcript, where the p41 isoform contains an extra
exon (exon 6b). These two isoforms yield two additional protein products due to an
N-terminal cytoplasmic extension of 16 residues, which results from an alternative
translation initiation site. The major human p33 isoform has an N-terminal cytosolic
tail of 30 amino acids, a transmembrane (TM) domain consisting of amino acid
31–56, and a C-terminal 160 residue luminal domain [3].
This chapter discusses MIF’s receptor CD74 and their central position in linking innate and
adaptive immune response in health and disease.
S. Becker-Herman • N. Gil • L. Radomir • I. Shachar, Ph.D. (*)
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
e-mail: [email protected]
© Springer International Publishing AG 2017 1
R. Bucala, J. Bernhagen (eds.), MIF Family Cytokines in Innate Immunity
and Homeostasis, Progress in Inflammation Research,
DOI 10.1007/978-3-319-52354-5_1
2 S. Becker-Herman et al.
The murine CD74 gene encodes two polypeptide chains, one of relative molecu-
lar mass of 31 kD (p31) and another less abundant 41 kD (p41) species [4, 5]. Exon
6b is alternatively spliced into the mRNA coding for the p41 isoform [6].
2 CD74 Function
Two main functions were described for CD74:
1. An MHC class II chaperone
2. Cell surface receptor for MIF
2.1 MHCII Chaperone
MHC class II molecules are heterodimeric complexes that present foreign antigenic
peptides on the cell surface of antigen-presenting cells (APCs) to CD4+ T cells [7–9].
MHC class II synthesis and assembly begins in the endoplasmic reticulum (ER)
with the non-covalent association of the MHC α and β chains with trimers of CD74.
Three MHC class II αß dimers bind sequentially to a trimer of CD74 to form a nona-
meric complex (αßCD74)3, which then exits the ER [10]. After being transported to
the trans-Golgi, the αßCD74 complex is diverted from the secretory pathway to the
endocytic system and ultimately to acidic endosome/lysosome-like structures called
MHC class II compartments (MIIC or CIIV) or to the cell surface. Cell surface CD74
is modified by the addition of chondroitin sulfate (CD74-CS) at amino acid position
201, and this form of CD74 is associated with MHC class II on the surface of antigen-
presenting cells [11–13]. Surface expression of newly synthesized CD74 followed by
its rapid internalization to the endosomal pathway has also been known for many
years. Experiments investigating cell surface CD74 are complicated by the fact that
CD74 on the cell surface is characterized by a very rapid turnover [14–16].
The N-terminal cytoplasmic tail of CD74 contains two extensively characterized
dileucine-based endosomal targeting motifs [17–19]. These motifs mediate its inter-
nalization from the plasma membrane and from the trans Golgi network. In the
endocytic compartments, CD74 is gradually proteolytically processed, leaving only
a small fragment, the class II-associated Ii chain peptide (CLIP), bound to the
released αß dimers. The final step for MHC class II expression requires interaction
of αßCLIP complexes with another class II-related αß dimer, called HLA-DM in the
human system, and H2-M in mice. Binding of this molecule drives out the residual
CLIP, rendering the αß dimers ultimately competent to bind antigenic peptides,
which are mainly derived from internalized antigens and are also delivered to the
endocytic pathway [20, 21]. The peptide-loaded class II molecules then leave this
compartment, by an unknown route, to be expressed on the cell surface and surveyed
by CD4+ T cells. Thus, CD74 was thought to function mainly as MHC class II
chaperone, which promotes ER exit of MHC class II molecules, directs them to
