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Division of Gastroenterology-Hepatology, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242
Substance P (SP) and somatostatin (SOM) are made at mucosal
surfaces and sites of inflammation. There is a SP/SOM immunoregulatory
circuit that modulates the IFN-
response in murine schistosomiasis.
SP enhances, while SOM decreases, IFN- secretion. Various
inflammatory mediators induce macrophages to make SOM, but no known
factor limits this expression. It was discovered that SP regulates SOM
synthesis. Splenocytes from normal, uninfected mice cultured with LPS,
IFN-, or IL-10 for 4 h strongly expressed SOM mRNA, but failed
to do so in the presence of SP. The inhibition with 10-9 M
SP was >85% shown by quantitative PCR. Also, splenocyte SOM content
decreased from 1048 ± 275 to <10 pg/4 x 108
cells following SP exposure. Immunohistochemistry identified SOM solely
within splenic macrophages following cytokine stimulation. Mice
infected with Schistosoma mansoni form granulomas in the
liver and intestines resulting from deposition of parasite eggs in
these organs. The granulomas contain macrophages that make SOM
constitutively. SP at 10-8 M decreased SOM mRNA expression
>90% in dispersed granuloma cells cultured for 4 h or longer.
Specific SP receptor antagonists blocked SP suppression of SOM
expression in splenocytes and dispersed granuloma cells, showing that
an authentic SP receptor mediated the regulation. Additional studies
revealed that IL-4 antagonized the SP effect in the spleen. It is
concluded that in granulomas and splenocytes from mice with
schistosomiasis and in splenocytes from uninfected animals that 1) SP
inhibits macrophage SOM induction and ongoing expression at the mRNA
and protein levels acting through the SP receptor, and 2) IL-4 can
antagonizes this SP effect.
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