16alpha-Bromoepiandrosterone (HE2000) limits non-productive inflammation and stimulates immunity in lungs.
16alpha-Bromoepiandrosterone (HE2000) is a synthetic steroid that limits non-productive inflammation, enhances protective immunity and improves survival in clinical studies of patients with human immunodeficiency virus (HIV), malaria and tuberculosis infections. We now show that HE2000 decreased nitric oxide production by lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Treatment with HE2000 also reduced non-productive inflammation associated with carrageenan-induced pleurisy and LPS-induced lung injury in mice. In the hapten-carrier reporter antigen popliteal lymph node assay, HE2000 increased absolute numbers of lymphocytes, antigen-presenting cells, hapten-specific immunoglobulin (Ig)M antibody-forming cells and shifted the interferon (IFN)-gamma/interleukin (IL)-4 balance towards IFN-gamma production. In the cystic fibrosis transmembrane conductance regulator (CFTR(-/-)) mouse model of acute Pseudomonas aeruginosa infection, treatment with HE2000 consistently reduced bacterial burden in lungs. All HE2000 effects were dose-dependent. In H1N1 infection in mice, HE2000 was safe but not effective as a monotherapy, as treatment did not effect survival. HE2000 reduced mortality related to excessive inflammation and opportunistic lung infections in animals and patients, and this might extend to those with H1N1 influenza infection.
Department of Biomedical Sciences, School of Medicine, University of Catania, Catania, Italy.
F
F
Nicoletti
D
D
Conrad
A
A
Wang
R
R
Pieters
K
K
Mangano
A
A
van Heeckeren
S K
SK
White
J
J
Frincke
C L
CL
Reading
D L
DL
Auci
D
D
Stickney
D055371:Acute Lung Injury / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control; D000738:Androsterone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002351:Carrageenan; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects; D053118:Influenza A Virus, H1N1 Subtype; D008070:Lipopolysaccharides; D008168:Lung / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D009894:Opportunistic Infections / Q000517:prevention & control; D009976:Orthomyxoviridae Infections / Q000188:drug therapy; D010998:Pleurisy / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D011552:Pseudomonas Infections / Q000517:prevention & control; D011550:Pseudomonas aeruginosa
C523751:16alpha-bromo-3beta-hydroxy-5alpha-androstan-17-one; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D002351:Carrageenan; D000738:Androsterone