Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice.
BACKGROUND
Inflammation may contribute to the pathogenesis of various forms of pulmonary hypertension (PH). Recent studies in patients with idiopathic PH or PH associated with underlying diseases suggest a role for interleukin-6 (IL-6).


METHODS
To determine whether endogenous IL-6 contributes to mediate hypoxic PH and lung inflammation, we studied IL-6-deficient (IL-6-/-) and wild-type (IL-6+/+) mice exposed to hypoxia for 2 weeks.


RESULTS
Right ventricular systolic pressure, right ventricle hypertrophy, and the number and media thickness of muscular pulmonary vessels were decreased in IL-6-/- mice compared to wild-type controls after 2 weeks' hypoxia, although the pressure response to acute hypoxia was similar in IL-6+/+ and IL-6-/- mice. Hypoxia exposure of IL-6+/+ mice led to marked increases in IL-6 mRNA and protein levels within the first week, with positive IL-6 immunostaining in the pulmonary vessel walls. Lung IL-6 receptor and gp 130 (the IL-6 signal transducer) mRNA levels increased after 1 and 2 weeks' hypoxia. In vitro studies of cultured human pulmonary-artery smooth-muscle-cells (PA-SMCs) and microvascular endothelial cells revealed prominent synthesis of IL-6 by PA-SMCs, with further stimulation by hypoxia. IL-6 also markedly stimulated PA-SMC migration without affecting proliferation. Hypoxic IL-6-/- mice showed less inflammatory cell recruitment in the lungs, compared to hypoxic wild-type mice, as assessed by lung protein levels and immunostaining for the specific macrophage marker F4/80, with no difference in lung expression of adhesion molecules or cytokines.


CONCLUSIONS
These data suggest that IL-6 may be actively involved in hypoxia-induced lung inflammation and pulmonary vascular remodeling in mice.
Savale
Laurent
L
INSERM U841, Université Paris XII, F94010 Créteil, France. laurent.savale@hmn.aphp.fr
Tu
Ly
L
Rideau
Dominique
D
Izziki
Mohamed
M
Maitre
Bernard
B
Adnot
Serge
S
Eddahibi
Saadia
S
D000818:Animals; D001794:Blood Pressure; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006976:Hypertension, Pulmonary / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000276:immunology; D000860:Hypoxia / Q000150:complications / Q000276:immunology* / Q000503:physiopathology; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000276:immunology / Q000473:pathology; D011014:Pneumonia / Q000276:immunology* / Q000503:physiopathology; D011651:Pulmonary Artery / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D013997:Time Factors
C508600:IL6 protein, human; D015850:Interleukin-6; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D050822:Cytokine Receptor gp130