Contribution of 5-HT2A receptor in nematode infection-induced murine intestinal smooth muscle hypercontractility.
OBJECTIVE
Enteric nematode infection induces a smooth muscle hypercontractility that depends on interleukin (IL)-4 and IL-13 activation of the signal transducer and activator of transcription (STAT) 6. Serotonin (5-HT) is involved in the physiologic regulation of gut function. The present study investigated the contribution of 5-HT and its receptors in nematode-induced intestinal smooth muscle hypercontractility.


METHODS
Mice were infected with Nippostrongylus brasiliensis (N brasiliensis) or Heligmosomoides polygyrus (H polygyrus) or injected intravenously with IL-13. Segments of jejunum were suspended in organ baths, and smooth muscle responses to 5-HT were determined in the presence or absence of specific 5-HT antagonists. IL-4, IL-13, and 5-HT receptor messenger RNA expressions were determined by real-time quantitative polymerase chain reaction.


RESULTS
5-HT evoked a modest contraction of smooth muscle in wild-type (WT) mice that was unaltered by the 5-HT2A antagonist ketanserin. N brasiliensis infection induced a smooth muscle hypercontractility to 5-HT that was abolished by 5-HT(2A) antagonists but not by other 5-HT antagonists. Infection-induced up-regulation of 5-HT2A expression was correlated with the smooth muscle hypercontractility to 5-HT. The infection-induced up-regulation of 5-HT2A in WT mice was observed also in IL-4(-/-) mice but was not seen in IL-13(-/-) or STAT6(-/-) mice. In addition, smooth muscle responses to 5-HT and 5-HT2A expression in WT mice were also enhanced by IL-13 or H polygyrus infection.


CONCLUSIONS
These data show that 5-HT2A is one of the molecules downstream from STAT6 activation that mediates changes in smooth muscle function. 5-HT2A represents a novel therapeutic target for modulating immune-mediated effects on intestinal motility.
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
Morimoto
Motoko
M
Elfrey
Justin E
JE
Madden
Kathleen B
KB
Finkelman
Fred D
FD
Shea-Donohue
Terez
T
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D007650:Ketanserin / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009122:Muscle Hypertonia / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D009130:Muscle, Smooth / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D009349:Nematode Infections / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D009559:Nippostrongylus / Q000302:isolation & purification; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology
D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D007650:Ketanserin