Macrophage migration inhibitory factor family proteins are multitasking cytokines in tissue injury

Abstract

The family of macrophage migration inhibitory factor (MIF) proteins in humans consist of MIF, its functional homolog D-dopachrome tautomerase (D-DT, also known as MIF-2) and the relatively unknown protein named DDT-like (DDTL). MIF is a pleiotropic cytokine with multiple properties in tissue homeostasis and pathology. MIF was initially found to associate with inflammatory responses and therefore established a reputation as a pro-inflammatory cytokine. However, increasing evidence demonstrates that MIF influences many different intra- and extracellular molecular processes important for the maintenance of cellular homeostasis, such as promotion of cellular survival, antioxidant signaling, and wound repair. In contrast, studies on D-DT are scarce and on DDTL almost nonexistent and their functions remain to be further investigated as it is yet unclear how similar they are compared to MIF. Importantly, the many and sometimes opposing functions of MIF suggest that targeting MIF therapeutically should be considered carefully, taking into account timing and severity of tissue injury. In this review, we focus on the latest discoveries regarding the role of MIF family members in tissue injury, inflammation and repair, and highlight the possibilities of interventions with therapeutics targeting or mimicking MIF family proteins.

Association Among MIF, IFIH1, and IL6 Gene Polymorphisms and Non-Segmental Vitiligo in a Chinese Han Population

“… 33 Multiple studies have found that the serum MIF concentration in patients with vitiligo vulgaris is significantly higher than the control group, and the serum MIF concentration in the active phase is higher compared with the stable phase. 6 , 15 , 34–36 Ma et al 37 and Garcia-Orozco et al 13 further found that MIF mRNA levels in skin lesions of patients with vitiligo were significantly increased, and serum MIF concentration and in situ expression were correlated with active non-segmental vitiligo, further suggesting that MIF plays a role in the pathogenesis of non-segmental vitiligo, especially in active patients. In our study, we found significant differences between patients and controls in terms of serum MIF levels.…”

“…Subsequently, MIF has been described as a proinflammatory factor with upstream regulatory roles in innate and adaptive immunity. 6 It has been shown to play a crucial role in several types of immune and autoimmune diseases. 7 , 8 MIF is mainly derived from macrophages and T cells and is secreted in response to several stimuli, including lipopolysaccharide (LPS), tumor necrosis factor (TNF)‐α, hypoxia, and oxidative stress.…”

Astaxanthin ameliorates serum level and spinal expression of macrophage migration inhibitory factor following spinal cord injury

“…Accordingly, MIF was first introduced as a proinflammatory cytokine, associated with inflammatory responses. However, recent evidence demonstrates that MIF influences cellular homeostasis, such as promotion of cellular survival, antioxidant signaling, and tissue repair (Song et al , 2022).…”

D‐dopachrome tautomerase in cardiovascular and inflammatory diseases—A new kid on the block or just another MIF?

“…19,[24][25][26] They also have an important pathogenic role in acute and chronic inflammatory conditions, cardiovascular diseases, lung diseases, neurodegenerative diseases, adipose tissue inflammation, and cancer, as summarized in previous review articles. [27][28][29][30][31][32][33][34][35][36][37][38][39][40] Curiously, both MIF and MIF-2 share a striking structural similarity and conserved N-terminal tautomerase pocket with a family of bacterial tautomerases, and display catalytic tautomerase activity in vitro [41][42][43] (Figure 1). Although the physiological relevance of this activity has yet to be elucidated, the existence of a catalytic pocket in the structure of these cytokines offers intriguing possibilities for the development of small molecule inhibitors.…”

“…Following the molecular identification of the Mif gene 21–23 a quarter of a century later, today, MIF as well as its more recently described structural homolog D‐dopachrome tautomerase (D‐DT; now also termed MIF‐2), are known as multifunctional cytokines and chemokines with key roles in host immunity and homeostasis 19,24–26 . They also have an important pathogenic role in acute and chronic inflammatory conditions, cardiovascular diseases, lung diseases, neurodegenerative diseases, adipose tissue inflammation, and cancer, as summarized in previous review articles 27–40 . Curiously, both MIF and MIF‐2 share a striking structural similarity and conserved N‐terminal tautomerase pocket with a family of bacterial tautomerases, and display catalytic tautomerase activity in vitro 41–43 (Figure 1).…”