Macrophage-specific eicosanoid synthesis inhibition and lipocortin-1 induction by glucocorticoids

Abstract

It has been suggested that the induction of lipocortin-1, a phospholipase A2-inhibitory protein, may mediate the anti-inflammatory action of glucocorticoids. We assessed the production of prostaglandin E2, thromboxane B2, and leukotriene B4 and the expression of lipocortin-1 in different populations of blood leukocytes and in alveolar macrophages (obtained by bronchoalveolar lavage) from patients with inflammatory lung diseases (bronchial asthma, n = 21; interstitial lung disease, n = 6) undergoing glucocorticoid treatment at clinically effective doses. No inhibition of eicosanoid production was observed in either whole blood or single populations of blood leukocytes (granulocytes and monocytes) stimulated with ionophore A-23187, N-formyl-L-methionyl-L-leucyl-L-phenylalanine, or zymosan. Conversely, eicosanoid production from alveolar macrophages (assessed in 9 cases) was significantly inhibited by glucocorticoids. After ionophore stimulation, eicosanoid production was as follows (in ng/ml): prostaglandin E2, 0.19 +/- 0.06 and 0.06 +/- 0.01; thromboxane B2, 2.9 +/- 0.9 and 0.5 +/- 0.1; leukotriene B4, 6.6 +/- 1.1 and 3.6 +/- 1.0, before and after treatment, respectively (P < 0.05 for all differences). Lipocortin-1 expression, determined by Western blot and enzyme immunoassay, was significantly (P < 0.05) stimulated in alveolar macrophages, but not in blood leukocytes, by glucocorticoid treatment. These results indicate that alveolar macrophages, at variance from blood leukocytes, are the most likely cell target for glucocorticoid-induced eicosanoid inhibition and lipocortin expression. We suggest that cell responsiveness to glucocorticoids is acquired during differentiation from monocyte to tissue macrophage.

Transfection of annexin 1 in monocytic cells produces a high degree of spontaneous and stimulated apoptosis associated with caspase‐3 activation

“…The expression of ANX1 is under the control of circulating glucocorticoid hormones (Vishwanath et al, 1992). Steroid induction of the protein as been demonstrated in several cell types (De Caterina et al, 1993;Raynal & Pollard, 1994), and supported by recent studies on the ANX1 promoter region (Solito et al, 1998a). Together these ®ndings support the notion of ANX1 as a mediator of antiin¯ammatory glucocorticoids, particularly with regard to leukocyte tracking and to regulation of pituitary hormone release (Flower, 1988;Lim et al, 1998).…”

An overview of the effects of annexin 1 on cells involved in the inflammatory process

“…The constitutive expression of ANXA1 mRNA and protein by macrophages has been shown reproducibly by many authors to increase following exposure to GC in vitro and in vivo (Ambrose et al 1992, De Caterina et al 1993, Peers et al 1993, Coméra et al 1995, Perretti & Flower 1996, Yang et al 1998, Hall et al 1999.…”

“…ANXA1 has been shown to be expressed by many different tissue specific macrophages including alveolar (Ambrose et al 1992, De Caterina et al 1993, peritoneal (Peers et al 1993), and synovial macrophages (Yang et al 1998) as well as microglial cells (Minghetti et al 1999), suggesting a regulatory role for the molecule in macrophage activity in general, that is not confined to any given tissue type. The constitutive expression of ANXA1 mRNA and protein by macrophages has been shown reproducibly by many authors to increase following exposure to GC in vitro and in vivo (Ambrose et al 1992, De Caterina et al 1993, Peers et al 1993, Coméra et al 1995, Perretti & Flower 1996, Yang et al 1998, Hall et al 1999.…”

“…Terminally differentiated macrophages such as human alveolar macrophages synthesise increased amounts of ANXA1 in response to GC treatment both in vitro (Ambrose et al 1992) and in vivo (De Caterina et al 1993) when compared to their peripheral blood monocyte precursors. Cellular sensitivity to GC therefore, is acquired during differentiation from blood monocyte to tissue macrophage and has been modelled in human U-937 monocytic cell lines, where GC induction of ANXA1 is only achieved when these cells are differentiated with phorbol ester (Solito et al 1991).…”

Suppressive effect of antiflammin-2 on compound 48/80-induced conjunctivitis Role of phospholipase A2s and inducible nitric oxide synthase

“…6,7 Pharmacological effects of corticosteroids are mediated by several steroid-induced proteins, e.g., lipocortins and uteroglobin. 8,9 Lipocortins mediate the antiinflammatory effects of corticosteroids, and uteroglobin has a PLA 2 -inhibitory effect. In the search for effective treatment of inflammatory diseases, PLA 2 s have received considerable attention because inhibition of PLA 2 s may effectively suppress the production of eicosanoids from both cyclooxygenase and lipoxygenase pathways.…”