Dysregulation of the IL-13 receptor system: a novel pathomechanism in pulmonary arterial hypertension.
BACKGROUND
Idiopathic pulmonary arterial hypertension (IPAH) is characterized by medial hypertrophy due to pulmonary artery smooth muscle cell (paSMC) hyperplasia. Inflammation is proposed to play a role in vessel remodeling associated with IPAH. IL-13 is emerging as a regulator of tissue remodeling; however, the contribution of the IL-13 system to IPAH has not been assessed.


OBJECTIVE
The objective of this study was to assess the possible contribution of the IL-13 system to IPAH.


METHODS
Expression and localization of IL-13, and IL-13 receptors IL-4R, IL-13Rα1, and IL-13Rα2 were assessed by real-time reverse transcription-polymerase chain reaction, immunohistochemistry, and flow cytometry in lung tissue, paSMC, and microdissected vascular lesions from patients with IPAH, and in lung tissue from rodents with hypoxia- or monocrotaline-induced pulmonary hypertension. A whole-genome microarray analysis was used to study IL-13-regulated genes in paSMC.


RESULTS
Pulmonary expression of the IL-13 decoy receptor IL-13Rα2 was up-regulated relative to that of the IL-13 signaling receptors IL-4R and IL-13Rα1 in patients with IPAH and in two animal models of IPAH. IL-13, signaling via STAT3 and STAT6, suppressed proliferation of paSMC by promoting G(0)/G(1) arrest. Whole-genome microarrays revealed that IL-13 suppressed endothelin-1 production by paSMC, suggesting that IL-13 controlled paSMC growth by regulating endothelin production. Ectopic expression of the il13ra2 gene resulted in partial loss of paSMC growth control by IL-13 and blunted IL-13 suppression of endothelin-1 production by paSMC, whereas small-interfering RNA knockdown of il13ra2 gene expression had the opposite effects.


CONCLUSIONS
The IL-13 system is a novel regulator of paSMC growth. Dysregulation of IL-13 receptor expression in IPAH may partially underlie smooth muscle hypertrophy associated with pathological vascular remodeling in IPAH.
Hecker
Matthias
M
Department of Internal Medicine (Pulmonology), University of Giessen Lung Center, Justus Liebig University, Giessen, Germany.
Zaslona
Zbigniew
Z
Kwapiszewska
Grazyna
G
Niess
Gero
G
Zakrzewicz
Anna
A
Hergenreider
Eduard
E
Wilhelm
Jochen
J
Marsh
Leigh M
LM
Sedding
Daniel
D
Klepetko
Walter
W
Lohmeyer
Jürgen
J
Dimmeler
Stefanie
S
Seeger
Werner
W
Weissmann
Norbert
N
Schermuly
Ralph T
RT
Kneidinger
Nikolaus
N
Eickelberg
Oliver
O
Morty
Rory E
RE
D000293:Adolescent; D000328:Adult; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology*; D007150:Immunohistochemistry; D018793:Interleukin-13 / Q000378:metabolism*; D053661:Interleukin-13 Receptor alpha1 Subunit / Q000378:metabolism; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism; D051381:Rats; D053660:Receptors, Interleukin-13 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000502:physiology*; D055815:Young Adult
D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D053663:Interleukin-13 Receptor alpha2 Subunit; D053660:Receptors, Interleukin-13