Glucocorticoid-induced MIF expression by human CEM T cells

Abstract

Macrophage migration inhibitory factor (MIF) is an upstream activator of the immune response that counter-regulates the immunosuppressive effects of glucocorticoids. While MIF is released by cells in response to diverse microbial and invasive stimuli, evidence that glucocorticoids in low concentrations also induce MIF secretion suggests an additional regulatory relationship between these mediators. We investigated the expression of MIF from the human CEM T cell line, which exists in two well-characterized, glucocorticoid-sensitive (CEM-C7) and glucocorticoid-resistant (CEM-C1) variant clones. Dexamethasone in low concentrations induced MIF secretion from CEM-C7 but not CEM-C1 T cells by a bell-shaped dose response that was similar to that reported previously for the release of MIF by monocytes/macrophages. Glucocorticoid stimulation of CEM-C7 T cells was accompanied by an MIF transcriptional response, which by promoter analysis was found to involve the GRE and ATF/CRE transcription factor binding sites. These data support a glucocorticoid-mediated MIF secretion response by T cells that may contribute to the regulation of the adaptive immune response.

Introduction

Macrophage migration inhibitory factor (MIF) is one of the first cytokine activities to be described [19], yet its upstream role in regulating the immune response has emerged relatively recently [13]. MIF circulates normally in plasma and its levels increase during physiologic stress, infection, or cancer [9], [13]. Experimental studies employing recombinant MIF, anti-MIF, or MIF knockout (MIF-KO) mice have established that this cytokine contributes to the immunopathogenesis of such disorders as endotoxemia and sepsis [9], [16], arthritis [5], [34], [37], inflammatory bowel disease [20], asthma [42], and tumor progression [39]. Certain of the pro-inflammatory properties of MIF, whether secreted locally or systemically, have been attributed to its ability to antagonize the immunosuppressive effects of glucocorticoids [14]. MIF regulates glucocorticoid action by several mechanisms; these include inducing sustained ERK1/2 MAP kinase activation, which leads to an increase in the translation of cytokine mRNAs [41], [56], inhibiting glucocorticoid-induced expression of the NF-κB inhibitor, IκB [18], and inhibiting glucocorticoid induction of MAP kinase phosphatase (MKP-1), which down-regulates the responses of the ERK1/2, p38, and JNK MAP kinases [1], [24], [51].

MIF is released by macrophages, synoviocytes, and neurons upon stimulation with low, physiologic levels of glucocorticoids [14], [54], [60], and these data are supported by studies of tissue MIF content after adrenalectomy or glucocorticoid administration [23]. Much of the MIF release response appears to be due to the secretion of protein from pre-formed, cytoplasmic stores [9], [23], [36], [45]. The observation that glucocorticoids, which are immunosuppressive [50], induce the release of a counter-regulating mediator such as MIF has focused attention on the role of this pathway in modulating the immune response [14], [24]. Of note, MIF normally circulates at its counter-regulating concentrations (2–10 ng/ml) and blood levels follow a circadian rhythm that is similar to the diurnal variation in plasma glucocorticoids [48], [49]. Whether MIF secretion from immune cells, the anterior pituitary gland, or other diurnally responsive tissues account for this circadian rhythm remains unknown [15], [29], [58]; nevertheless, these observations have led to the concept that MIF and glucocorticoids may act in a regulatory “dyad” to control the setpoint and the magnitude of the immune response [13], [14], [24]. That MIF functions as a physiological regulator of glucocorticoid action also has prompted pharmacologic approaches at targeting MIF for steroid-dependent, chronic inflammatory conditions [12], [35], [43].

Prior reports of a specific MIF secretion response from monocytes/macrophages stimulated with low, physiologic levels of glucocorticoids [14] together with increasing evidence that MIF influences the differentiation of the adaptive T cell response [8], [42] prompted us to examine more closely MIF production by human T cells. We studied MIF protein release and mRNA expression in the two closely related human T cell lines, CEM-C1 and CEM-C7, which differ in their sensitivity to glucocorticoid-dependent responses downstream of the glucocorticoid receptor [57].