Macrophage migration inhibitory factor exhibits a pronounced circadian rhythm relevant to its role as a glucocorticoid counter‐regulator

Abstract

SummaryIn humans, maximal expression of T helper 1 cytokines coincide with the nocturnal nadir of plasma cortisol, whereas T helper 2 cytokine responses are dominant during day-time. The pro-inflammatory cytokine, macrophage migration inhibitory factor counter-regulates glucocorticoid-mediated immune suppression. To determine the relationship between cortisol and macrophage migration inhibitory factor, healthy volunteers had blood drawn hourly for 24 h for measurement of plasma cortisol and basal-and stimulated-macrophage migration inhibitory factor. Similar to cortisol, macrophage migration inhibitory factor peaked during the late morning whereas interferon-γ, tumour necrosis factor-α, interleukin-1 and interleukin-12 demonstrated a nocturnal peak. After oral cortisone, plasma macrophage migration inhibitory factor rose 2-4-fold, whereas the other cytokines decreased. There was no correlation between cortisol during the insulin tolerance test and plasma macrophage migration inhibitory factor. The late morning peak of macrophage migration inhibitory factor, by antagonizing cortisol-mediated pro-inflammatory cytokine suppression may prolong the duration of early morning inflammation. These observations explain the beneficial role of macrophage migration inhibitory factor neutralization in models of inflammatory arthritis.

Obesity, macrophage migration inhibitory factor, and weight loss

“…2,9,[13][14][15][16] Although our study population had considerably higher mean MIF values than those reported in other studies and our small reference group, most of the weight management participants did not have a markedly elevated plasma MIF concentration. Thus, the elevated mean group MIF in the weight management group was due to small portion of the total sample, as supported by the distribution of MIF (Figure 1).…”

High expression levels of macrophage migration inhibitory factor sustain the innate immune responses of neonates

“…Attractive candidates are steroid hormones. Indeed, estradiol, progesterone, and glucocorticoids are expressed at particularly high levels during the neonatal period; have a short half-life; and stimulate MIF production by immune cells in vitro and in vivo (27,47,48). Because newborn whole blood and monocytes show somewhat different MIF secretion profiles in response to E. coli and GBS, T cells, B cells, neutrophils, eosinophils, and platelets may participate to release MIF in response to microbial stimulation (49)(50)(51)(52).…”

Identification of Iguratimod as an Inhibitor of Macrophage Migration Inhibitory Factor (MIF) with Steroid-sparing Potential

“…In addition, MIF release is triggered rather than suppressed by glucocorticoids in multiple cell types, and plasma MIF levels fluctuate in a circadian fashion that mirrors plasma levels of glucocorticoids (19,22). These properties have led some to suggest that MIF's primary function is as an endogenous counter-regulator of glucocorticoids (23).…”

“…MIF is ubiquitously expressed and detectable in plasma at nanogram/ml concentrations (22,33). Although MIF deletion is beneficial in multiple disease conditions, the MIF KO animal is healthy and long-lived, and in the absence of intervention it has no associated health problems (8,10,34).…”