Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2003 Jan;162(1):47-56.
doi: 10.1016/S0002-9440(10)63797-2.

Regulation of macrophage migration inhibitory factor expression by glucocorticoids in vivo

Gunter Fingerle-Rowson  1 , Peter Koch, Rachel Bikoff, Xinchun Lin, Christine N Metz, Firdaus S Dhabhar, Andreas Meinhardt, Richard Bucala
Affiliations

Regulation of macrophage migration inhibitory factor expression by glucocorticoids in vivo

Gunter Fingerle-Rowson et al. Am J Pathol. 2003 Jan.

Abstract

Glucocorticoid hormones are important anti-inflammatory agents because of their anti-inflammatory and proapoptotic action within the immune system. Their clinical usefulness remains limited however by side effects that result in part from their growth inhibitory action on sensitive target tissues. The protein mediator, macrophage migration inhibitory factor (MIF), is an important regulator of the host immune response and exhibits both glucocorticoid-antagonistic and growth-regulatory properties. MIF has been shown to contribute significantly to the development of immunopathology in several models of inflammatory disease. Although there is emerging evidence for a functional interaction between MIF and glucocorticoids in vitro, little is known about their reciprocal influence in vivo. We investigated the expression of MIF in rat tissues after ablation of the hypothalamic-pituitary-adrenal axis and after high-dose glucocorticoid administration. MIF expression is constitutive and independent of the influence of adrenal hormones. Hypophysectomy and the attendent loss of pituitary hormones, by contrast, decreased MIF protein content in the adrenal gland. Administration of dexamethasone was found to increase MIF protein expression in those organs that are considered to be sensitive to the growth inhibitory effects of glucocorticoids (immune and endocrine tissues, skin, and muscle). This increase was most likely because of a posttranscriptional regulatory effect because tissue MIF mRNA levels were not influenced by dexamethasone treatment. Finally, MIF immunoneutralization enhanced lymphocyte egress from blood during stress-induced lymphocyte redistribution, consistent with a functional interaction between MIF and glucocorticoids on immune cell trafficking in vivo. These findings suggest a role for MIF in both the homeostatic and physiological action of glucocorticoids in vivo.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
MIF protein expression in Hx and Adx rats. Western blotting of various tissues from Hx rats, Adx rats, and sham-operated controls (n = 3 per group) at day 10 after surgery. Equal amounts of total protein were loaded. Two representative examples are given for each tissue and experimental condition.
Figure 2.
Figure 2.
MIF protein expression in Hx rats. Protein lysates from the adrenals of Hx and sham-operated controls were compared by Western analysis for their content of MIF and actin (n = 3 per group). MIF expression in adrenals at day 10 after surgery from Hx animals was significantly reduced when assessed by densitometric analysis (P < 0.001, Student’s t-test).
Figure 3.
Figure 3.
Dexamethasone-induced changes in MIF protein expression in various rat tissues. The content of MIF protein from dexamethasone-treated and saline-treated rats was determined in a semiquantitative manner by Western blotting and densitometric analysis. Data are the mean and SD of the change of MIF protein in dexamethasone-treated rats compared to the saline controls. 1, no change; 2, twofold; 3, threefold; and so forth. *, Statistically significant with P < 0.05, Student’s t-test.
Figure 4.
Figure 4.
MIF protein expression in representative organs after dexamethasone administration. A and B: Rats (n = 3 per group) received a single injection of saline (control) or dexamethasone at 10 mg/kg (Dex). MIF, signal regulatory protein, and actin contents in organ lysates were measured by Western blotting as described in Materials and Methods. C: Skin and muscle show a slight increase in MIF protein content in rats treated for 5 days with dexamethasone. Representative analyses from four different animals are shown.
Figure 5.
Figure 5.
Plasma MIF levels during dexamethasone treatment. Dexamethasone (10 mg/kg, Dex) or saline (control) was administered intraperitoneally to Sprague-Dawley rats (n = 3 per group) at 9 a.m. each morning for 5 days. MIF levels were measured by Western blotting at 0, 6, 12, 24, and 96 hours after first injection. Plasma was pooled for the analysis of each time point. rMIF (10 ng) was loaded as control.
Figure 6.
Figure 6.
Immunohistochemical localization of glucocorticoid-induced changes in MIF protein expression. Tissues from dexamethasone-treated rats were compared with saline-treated controls. MIF protein was detected in paraformaldehyde-fixed sections by immunohistochemistry. MIF expression increased in the medullary cells of the thymus (A, B), in the red and white pulp of the spleen (C, D), in the epithelium of the epididymis (E, F), and in the cortex of the adrenal gland (G, H).
Figure 7.
Figure 7.
Northern blotting analysis of MIF mRNA expression. Total RNA from saline-treated (−) and dexamethasone-treated (+) rats (n = 3 per group) was analyzed using specific cDNA probes for MIF, GAPDH, and β-actin. Shown are representative blots from the adrenal (12 hours after dexamethasone administration), and from the spleen and the thymus (24 hours after dexamethasone administration). The MIF mRNA levels do not appear to be increased relative to the mRNA for GAPDH and β-actin. Protein levels of β-actin were not altered by dexamethasone treatment (Figure 4) ▶ .
Figure 8.
Figure 8.
Effect of anti-MIF treatment on stress-induced leukocyte redistribution in vivo. Young adult male Sprague Dawley rats were injected with 3 mg/kg of anti-MIF or an isotype control IgG (n = 3 per group) 4 hours before a 2-hour stress by restraint experiment. Total white blood cell and differentials were determined before, during, and after stress on a hematology analyzer. Values are mean ± SD. *, Significant with P < 0.05 in a Student’s t-test.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Swope MD, Lolis E: Macrophage migration inhibitory factor: cytokine, hormone, or enzyme? Rev Physiol Biochem Pharmacol 1999, 139:1-32 - PubMed
    1. David J: Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction. Proc Natl Acad Sci USA 1966, 56:72-77 - PMC - PubMed
    1. Bloom BR, Bennett B: Mechanism of a reaction in vitro associated with delayed-type hypersensitivity. Science 1966, 111:514-521 - PubMed
    1. Metz CN, Bucala R: MIF. 2000:pp 703-716 Academic Press, San Diego CA
    1. Bernhagen J, Calandra T, Cerami A, Bucala R: Macrophage migration inhibitory factor is a neuroendocrine mediator of endotoxaemia. Trends Microbiol 1994, 2:198-201 - PubMed

Publication types

MeSH terms