Corticosteroid inhibition of macrophage inflammatory protein-1 alpha in human monocytes and alveolar macrophages

Abstract

One of the major inducible cytokines secreted by mononuclear phagocytes is macrophage inflammatory protein 1 (MIP-1), which consists of two homologous polypeptides, MIP-1 alpha and MIP-1 beta. MIP-1 alpha possesses chemotactic and stimulatory activities for lymphocytes, eosinophils, and monocytes and may play a role in various pulmonary inflammatory conditions. We investigated the expression and release of MIP-1 alpha from human peripheral blood monocytes (PBM) and alveolar macrophages (AM) after stimulation with lipopolysaccharide (LPS), interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha, and interferon-gamma and the inhibitory effects of corticosteroids. LPS and IL-1 beta only enhanced MIP-1 alpha mRNA and protein in a dose- and time-dependent fashion. Dexamethasone (10(-9) to 10(-4) M) inhibited the basal and induced production and expression of MIP-1 alpha. In PBM, dexamethasone (10(-6) M) reduced LPS- and IL-1 beta-stimulated production of MIP-1 alpha protein by 50 and 63%, respectively, maximally at 24 h, whereas the inhibition of mRNA expression occurred maximally at 4 h. Similar trends were observed for AM. MIP-1 alpha mRNA decay was only slightly decreased in the presence of dexamethasone. Inhibition of LPS-induced MIP-1 alpha mRNA by dexamethasone was attenuated by the protein synthesis inhibitor cycloheximide, indicating the involvement of a protein intermediate. Corticosteroids are a potent inhibitor of IL-1 beta- and LPS-induced expression of MIP-1 alpha through mechanisms involving mainly inhibition of transcription and to a minor degree by reducing mRNA stability. Corticosteroids may be effective anti-inflammatory agents by preventing the expression of chemokines such as MIP-1 alpha.

Targeting dexamethasone to Kupffer cells: Effects on liver inflammation and fibrosis in rats

“…The decrease caused by Dexa 5 -Man 10 -HSA was attributable to less activated KC and less infiltrating granulocytes as found by immunohistochemical analysis (data not shown). Dexamethasone is known to inhibit both ROS synthesis and the synthesis of chemotactic factors by KC, [40][41][42] thus confirming effective delivery of dexamethasone into the KC. Equimolar amounts of free dexamethasone did not reduce the amount of ROSproducing cells, showing the increased efficacy of targeted dexamethasone, despite the cell-activating effects of the carrier Man 10 -HSA.…”

Anti-inflammatory functions of glucocorticoid-induced genes

“…Targets of such regulation include COX-2 (Chivers et al, 2006;Lasa et al, 2001;Newton et al, 1998;Ristimaki et al, 1996), TNF (Han et al, 1990;Kontoyiannis et al, 1999;Swantek et al, 1997), vascular endothelial growth factor (Gille et al, 2001), interferon β (Peppel et al, 1991), colony stimulating factor 2 (CSF2) (Bergmann et al, 2004;Tobler et al, 1992;Tran et al, 2005), IL-5 (Staples et al, 2003), IL-6 (Amano et al, 1993;Tobler et al, 1992), IL-1α and -1β (Amano et al, 1993;Lee et al, 1988), inducible nitric oxide synthase (Korhonen et al, 2002) and several chemokines (Berkman et al, 1995;Brach et al, 1992;Chang et al, 2001;Chaudhary and Avioli, 1996;Chivers et al, 2006;Mukaida et al, 1991;Poon et al, 1999;Stellato et al, 1999;Tobler et al, 1992). The majority of these mRNAs have in common the presence of adenylate/uridylate-rich elements (AREs) in their 3' untranslated regions (UTRs).…”

Is there an interaction between interleukin-10 and interleukin-22?

“…In these cells, IL-10 inhibits the production of proinflammatory cytokines and chemokines and downregulates the expression of MHC class II and costimulatory molecules thereby repressing the T-cell-stimulating capacity of these cells. [2][3][4][5][6][7][8][9] Furthermore, IL-10 increases the surface IgG receptor expression and promotes phagocytosis by monocytes. 10 All these IL-10 effects are mediated by the IL-10 receptor complex that consists of ligand-specific IL-10R1 and accessory IL-10R2.…”