Macrophage Migration Inhibitory Factor Induces B Cell Survival by Activation of a CD74-CD44 Receptor Complex

Abstract

Macrophage migration inhibitory factor (MIF) is an upstream activator of innate immunity that regulates subsequent adaptive responses. It was previously shown that in macrophages, MIF binds to a complex of CD74 and CD44, resulting in initiation of a signaling pathway. In the current study, we investigated the role of MIF in B cell survival. We show that in B lymphocytes, MIF initiates a signaling cascade that involves Syk and Akt, leading to NF-B activation, proliferation, and survival in a CD74-and CD44-dependent manner. Thus, MIF regulates the adaptive immune response by maintaining the mature B cell population.An established paradigm divides the immunologic response into innate and adaptive components, with critical interactions between the two producing normal immunity or immunopathology. The innate response represents the earliest host response to invasive pathogens by cells such as monocytes/ macrophages, whereas the adaptive response includes the development of antigen-specific responses, antibody production, and immunologic memory. Significant attention is currently focused on the molecules that link innate and adaptive immunity, and that may critically regulate immune responses or the development of inflammatory/autoimmune diseases.CD74 is a non-polymorphic type II integral membrane protein that is expressed on antigen presenting cells including macrophages and B cells. It has a short N-terminal cytoplasmic tail of 28 amino acids, followed by a single 24-amino acid transmembrane region and an ϳ150-amino acid lumenal domain. The CD74 chain was considered initially to function mainly as a major histocompatibility complex class II chaperone, which promotes endoplasmic reticulum exit of major histocompatibility complex class II molecules, directs them to endocytic compartments, prevents peptide binding in the endoplasmic reticulum, and contributes to peptide editing in the major histocompatibility complex class II compartment (1). A small proportion of CD74 is modified by the addition of chondroitin sulfate (CD74-CS), and this form of CD74 is expressed on the surface of antigen presenting cells, including monocytes and B cells. Antibody blocking studies additionally have shown that CD74-CS interacts with CD44, which activates a Src-kinase dependent signaling pathway (2).It was previously shown that macrophage migration inhibitory factor (MIF) 3 binds to the CD74 extracellular domain on macrophages, a process that results in initiation of a signaling pathway (3). MIF accounts for one of the first cytokine activities to have been described (4). MIF promotes monocyte/macrophage activation and is required for the optimal expression of tumor necrosis factor, interleukin-1, and prostaglandin E 2 (5-7). MIF-activated macrophages are more phagocytic and better able to destroy intracellular pathogens, such as Leishmania (8, 9). These activating functions have been verified in MIF knock-out mice (6, 10, 11). The role of MIF in adaptive immunity is less well characterized, but neutralization of MIF using specific anti...

Trichomonas vaginalis homolog of macrophage migration inhibitory factor induces prostate cell growth, invasiveness, and inflammatory responses

“…As prostate cancer progresses, levels of HuMIF and CD74 increase (10), resulting in a positive feedback loop that leads to inflammation and activation of cell proliferation and survival pathways (51)(52)(53). TvMIF could add fuel to this fire by stimulating CD74, because we show that TvMIF binding to CD74 can activate downstream ERK and Akt/BAD pathways.…”

Migration Inhibitory Factor Enhances Inflammation via CD74 in Cartilage End Plates with Modic Type 1 Changes on MRI

“…CD74 immunostaining is increased in inflammatory diseases, and MIF binding to CD74 induces nuclear factor j-light-chain-enhancer of activated B cells (NF-jB) and the secretion of inflammatory cytokines [7]. CD74 can be stimulated by CD74Ab or MIF to increase the DNA and protein synthesis in the B cells through the NF-jB signal pathway [16]. We found that CD74 activation with CD74Ab leads to the secretion of the inflammatory cytokines IL-6, IL-8, and PGE2 in a dose-dependent manner.…”

Novel Anti-inflammatory Activity of Epoxyazadiradione against Macrophage Migration Inhibitory Factor

“…It is reported that binding of MIF to CD74⅐CD44 complex leads to the release of the cytosolic domain of CD74 (CD74 ICD), which initiates the signaling pathway, and consequently to activation of NF-B (73). Treatment of cells with ISO-1, an antagonist of human MIF, reduced NF-B activation, indicating a role of MIF in NF-B (73) activation.…”

“…NF-B translocation to the nucleus by different proinflammatory cytokines including huMIF has already been reported (24,(73)(74)(75)(76)(77). To further evaluate the effect of epoxyazadiradione on MIF-induced translocation of NF-B to the nucleus, an EMSA was performed.…”