SUBSTANCE-P REGULATES SOMATOSTATIN EXPRESSION IN INFLAMMATION

Substance P (SP) and somatostatin (SOM) are made at mucosal surfaces a nd sites of inflammation. There is a SP/SOM immunoregulatory circuit t hat modulates the IFN-gamma response in murine schistosomiasis. SP enh ances, while SOM decreases, IFN-gamma secretion. Various inflammatory mediators induce macrophages to make SOM, but no known factor limits t his expression, It was discovered that SP regulates SOM synthesis. Spl enocytes from normal, uninfected mice cultured with LPS, IFN-gamma, 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 qua ntitative PCR, Also, splenocyte SOM content decreased from 1048 +/- 27 5 to <10 pg/4 x 10(8) cells following SP exposure, Immunohistochemistr y 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 i n these organs, The granulomas contain macrophages that make SOM const itutively. SP at 10(-8) M decreased SOM mRNA expression >90% in disper sed granuloma cells cultured for 4 h or longer. Specific SP receptor a ntagonists blocked SP suppression of SOM expression in splenocytes and dispersed granuloma cells, showing that an authentic SP receptor medi ated the regulation, Additional studies revealed that IL-4 antagonized the SP effect in the spleen. It is concluded that in granulomas and s plenocytes from mice with schistosomiasis and in splenocytes from unin fected animals that 1) SP inhibits macrophage SOM induction and ongoin g expression at the mRNA and protein levels acting through the SP rece ptor, and 2) IL-4 can antagonizes this SP effect.