Macrophage-specific eicosanoid synthesis inhibition and lipocortin-1 induction by glucocorticoids.
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.
De Caterina
R
R
Laboratory for Thrombosis and Vascular Research, University of Pisa, Italy.
Sicari
R
R
Giannessi
D
D
Paggiaro
P L
PL
Paoletti
P
P
Lazzerini
G
G
Bernini
W
W
Solito
E
E
Parente
L
L
D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D017305:Annexin A1 / Q000096:biosynthesis*; D001249:Asthma / Q000097:blood / Q000378:metabolism; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D015777:Eicosanoids / Q000096:biosynthesis*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007958:Leukocyte Count; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008171:Lung Diseases / Q000097:blood / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D013481:Superoxides / Q000378:metabolism
D017305:Annexin A1; D015777:Eicosanoids; D005938:Glucocorticoids; D013481:Superoxides