title: Synthesis of glucocorticoid-induced leucine zipper (GILZ) by macrophages: an anti-inflammatory and immunosuppressive mechanism shared by glucocorticoids and IL-10.
abstract: Glucocorticoids and interleukin 10 (IL-10) prevent macrophage activation. In murine lymphocytes, glucocorticoids induce expression of glucocorticoid-induced leucine zipper (GILZ), which prevents the nuclear factor kappaB (NF-kappaB)-mediated activation of transcription. We investigated whether GILZ could account for the deactivation of macrophages by glucocorticoids and IL-10. We found that GILZ was constitutively produced by macrophages in nonlymphoid tissues of humans and mice. Glucocorticoids and IL-10 stimulated the production of GILZ by macrophages both in vitro and in vivo. Transfection of the macrophagelike cell line THP-1 with the GILZ gene inhibited the expression of CD80 and CD86 and the production of the proinflammatory chemokines regulated on activation normal T-cell expressed and secreted (CCL5) and macrophage inflammatory protein 1alpha (CCL3). It also prevented toll-like receptor 2 production induced by lipopolysaccharide, interferongamma, or an anti-CD40 mAb, as well as NF-kappaB function. In THP-1 cells treated with glucocorticoids or IL-10, GILZ was associated with the p65 subunit of NF-kappaB. Activated macrophages in the granulomas of patients with Crohn disease or tuberculosis do not produce GILZ. In contrast, GILZ production persists in tumor-infiltrating macrophages in Burkitt lymphomas. Therefore, GILZ appears to play a key role in the anti-inflammatory and immunosuppressive effects of glucocorticoids and IL-10. Glucocorticoid treatment stimulates GILZ production, reproducing an effect of IL-10, a natural anti-inflammatory agent. The development of delayed-type hypersensitivity reactions is associated with the down-regulation of GILZ gene expression within lesions. In contrast, the persistence of GILZ gene expression in macrophages infiltrating Burkitt lymphomas may contribute to the failure of the immune system to reject the tumor.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U131, Institut Paris-Sud sur les Cytokines, Clamart, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Berrebi
authors.forename: Stefano
authors.initials: S
authors.lastname: Bruscoli
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cohen
authors.forename: Arnaud
authors.initials: A
authors.lastname: Foussat
authors.forename: Graziella
authors.initials: G
authors.lastname: Migliorati
authors.forename: Laurence
authors.initials: L
authors.lastname: Bouchet-Delbos
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Maillot
authors.forename: Alain
authors.initials: A
authors.lastname: Portier
authors.forename: Jacques
authors.initials: J
authors.lastname: Couderc
authors.forename: Pierre
authors.initials: P
authors.lastname: Galanaud
authors.forename: Michel
authors.initials: M
authors.lastname: Peuchmaur
authors.forename: Carlo
authors.initials: C
authors.lastname: Riccardi
authors.forename: Dominique
authors.initials: D
authors.lastname: Emilie
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000187:drug effects; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000187:drug effects; D051940:B7-2 Antigen; D018925:Chemokines / Q000096:biosynthesis; D029721:Drosophila Proteins; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007108:Immune Tolerance; D007249:Inflammation / Q000276:immunology; D016753:Interleukin-10 / Q000494:pharmacology; D016350:Leucine Zippers / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009928:Organ Specificity; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000187:drug effects; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014157:Transcription Factors / Q000096:biosynthesis* / Q000187:drug effects / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; D018925:Chemokines; D029721:Drosophila Proteins; C498608:Dsip1 protein, mouse; D005938:Glucocorticoids; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C404226:TSC22D3 protein, human; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014157:Transcription Factors; D016753:Interleukin-10