Plasma Levels of Macrophage Migration Inhibitory Factor and d-Dopachrome Tautomerase Show a Highly Specific Profile in Early Life

Abstract

Macrophage migration inhibitory factor (MIF) is a pleiotropic, constitutively expressed, pro-inflammatory cytokine and an important regulator of immune responses. d-dopachrome tautomerase (DDT), a newly described member of the MIF protein superfamily, shares sequence homology and biological activities with MIF. We recently reported that high expression levels of MIF sustain innate immune responses in newborns. Here, we elected to further characterize age-dependent MIF expression and to define whether DDT shares a similar expression profile with MIF. Therefore, we delineated the circulating concentrations of MIF and DDT throughout life using a large cohort of 307 subjects including fetuses, newborns, infants, children, and adults. Compared to levels measured in healthy adults (median: 5.7 ng/ml for MIF and 16.8 ng/ml for DDT), MIF and DDT plasma concentrations were higher in fetuses (median: 48.9 and 29.6 ng/ml), increased further at birth (median: 82.6 and 52.0 ng/ml), reached strikingly elevated levels on postnatal day 4 (median: 109.5 and 121.6 ng/ml), and decreased to adult levels during the first months of life. A strong correlation was observed between MIF and DDT concentrations in all age groups (R = 0.91, P < 0.0001). MIF and DDT levels correlated with concentrations of vascular endothelial growth factor, a protein upregulated under low oxygen tension and implicated in vascular and lung development (R = 0.70, P < 0.0001 for MIF and R = 0.65, P < 0.0001 for DDT). In very preterm infants, lower levels of MIF and DDT on postnatal day 6 were associated with an increased risk of developing bronchopulmonary dysplasia and late-onset neonatal sepsis. Thus, MIF and DDT plasma levels show a highly specific developmental profile in early life, supporting an important role for these cytokines during the neonatal period.

MIF and D-DT are potential disease severity modifiers in male MS subjects

“…Our human data also demonstrate a strong correlation between MIF and D-DT expression in plasma and CNS. Such correlation was demonstrated previously in sepsis patients and healthy subjects (50) in concert with MIF and D-DT cooperative regulation of lung carcinoma cells (51). The two proteins share 34% amino acid sequence identity and the common MIF superfamily protein fold (27).…”

Toll-like Receptors Regulate MIF Expression in Benign Lymphoepithelial Lesion of the Lacrimal Gland

“…Indeed, the primary fibroblast cells BLELp1 and BLELp2 secreted MIF respectively at a concentration of 4.34ng/ml and 1.2ng/ml while the MIF released by the tissue-derived lymphocytes was dosed at 2.09ng/ml. These results are in accordance with the concentration of MIF reported in normal physiological conditions in adult population [29].…”

MIF family cytokines in cardiovascular diseases and prospects for precision-based therapeutics

“…In healthy adults, circulating MIF is present in the plasma in the 2–6 ng/mL range and a circadian rhythm with elevated MIF plasma levels in the morning has been observed [14]. While MIF was first cloned from pituitary cells and stress stimuli promote its release into the circulation [15, 16], the major cellular or tissue source of circulating MIF remains unknown [17]. Immune cells such as monocytes, macrophages, neutrophils, dendritic cells, mast cells, eosinophils, platelets, T- and B-cells express MIF, and the protein is broadly expressed in cells at the outer lining of tissues such as endothelial and epithelial cells, as well as in cardiomyocytes, adipocytes and stromal cells [18].…”