Th2 cytokine-induced alterations in intestinal smooth muscle function depend on alternatively activated macrophages.
OBJECTIVE
Enteric nematode infection induces a strong type 2 T helper cell (Th2) cytokine response characterized by increased infiltration of various immune cells, including macrophages. The role of these immune cells in host defense against nematode infection remains poorly defined. The present study investigated the role of macrophages and the arginase pathway in nematode-induced changes in intestinal smooth muscle function and worm expulsion.


METHODS
Mice were infected with Nippostrongylus brasiliensis and treated with clodronate-containing liposome to deplete macrophages or given S-(2-boronoethyl)-I-cysteine in drinking water to inhibit arginase activity. Segments of intestinal smooth muscle were suspended in organ baths to determine responses to acetylcholine, 5-hydroxytryptamine, or nerve stimulation. The phenotype of macrophages was monitored by measuring mRNA expression of the specific molecular markers by real-time polymerase chain reaction or viewed by immunofluorescence staining.


RESULTS
Infection increased the infiltration of macrophages and up-regulation alternatively activated macrophage markers by a mechanism dependent on interleukin-4 (IL-4) or interleukin-13 (IL-13) activation of signal transducer and activator of transcription 6. Elimination of alternatively activated macrophages blocked smooth muscle hypercontractility and the increased smooth muscle thickness, and impaired worm expulsion. In addition, specific inhibition of arginase activity interfered with smooth muscle contractility, but only partially affected the protective immunity of the host.


CONCLUSIONS
These data show that the phenotype of macrophages is determined by the local immune environment and that alternatively activated macrophages play a major role in the effects of Th2 cytokines, IL-4 and IL-13, on intestinal smooth muscle function.
Zhao
Aiping
A
Department of Medicine and the Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Urban
Joseph F
JF
Anthony
Robert M
RM
Sun
Rex
R
Stiltz
Jennifer
J
van Rooijen
Nico
N
Wynn
Thomas A
TA
Gause
William C
WC
Shea-Donohue
Terez
T
D000818:Animals; D001119:Arginase / Q000378:metabolism; D005260:Female; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007422:Intestines / Q000276:immunology* / Q000469:parasitology; D008264:Macrophages / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D016513:Mice, SCID; D009130:Muscle, Smooth / Q000276:immunology* / Q000469:parasitology; D009559:Nippostrongylus; D017206:Strongylida Infections / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D015854:Up-Regulation / Q000276:immunology
D018793:Interleukin-13; D015847:Interleukin-4; D001119:Arginase