IL-12 gene transfer alters gut physiology and host immunity in nematode-infected mice.
Immune responses elicited by nematode parasite infections are characterized by T helper 2 (Th2) cell induction. The immunologic basis for changes in intestinal physiology accompanying nematode infection is poorly understood. This study examined whether worm expulsion and associated goblet cell hyperplasia and muscle contractility share a similar immune basis by shifting the response from Th2 to Th1 using interleukin-12 (IL-12) overexpression. We used a single administration of recombinant adenovirus vector expressing IL-12 (Ad5IL-12) in Trichinella spiralis-infected mice. Ad5IL-12 administered 1 day after infection prolonged worm survival and inhibited infection-induced muscle hypercontractility and goblet cell hyperplasia. This was correlated with upregulated interferon-gamma (IFN-gamma) expression and downregulated IL-13 expression in the muscularis externa layer. We also observed increased IFN-gamma production and decreased IL-4 and IL-13 production from in vitro stimulated spleen and mesenteric lymph node cells of infected Ad5IL-12-treated mice. These results indicate that transfer and overexpression of the IL-12 gene during Th2-based nematode infection shifts the immune response toward Th1 and delays worm expulsion. Moreover, the immune response shift abrogated the physiological responses to infection, attenuating both muscle hypercontractility and goblet cell hyperplasia. These findings strongly indicate that worm expulsion, muscle hypercontractility, and goblet cell hyperplasia share a common immunologic basis and may be causally linked.
Khan
W I
WI
Intestinal Disease Research Program, McMaster University, Hamilton, Ontario, Canada L8N 3Z5.
Blennerhassett
P A
PA
Deng
Y
Y
Gauldie
J
J
Vallance
B A
BA
Collins
S M
SM
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015870:Gene Expression / Q000276:immunology; D018014:Gene Transfer Techniques; D020397:Goblet Cells / Q000276:immunology* / Q000469:parasitology* / Q000473:pathology; D006790:Host-Parasite Interactions / Q000276:immunology; D006965:Hyperplasia; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000097:blood / Q000235:genetics* / Q000276:immunology; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology; D008297:Male; D051379:Mice; D009130:Muscle, Smooth / Q000276:immunology / Q000469:parasitology; D009195:Peroxidase / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D017160:Trichinella spiralis; D014235:Trichinellosis / Q000276:immunology*
D018793:Interleukin-13; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D009195:Peroxidase