IL-4 inhibits vasoactive intestinal peptide production by macrophages.
In schistosomiasis, eggs induce granulomas that have a vasoactive intestinal peptide (VIP) immunoregulatory circuit. This study explored the regulation of VIP production at sites of inflammation. Splenocytes from uninfected C57BL/6 mice expressed VIP mRNA and protein, which stopped following egg deposition. Eggs induce a Th2 response, suggesting that Th2 cytokines like interleukin (IL)-4 can regulate VIP. To address this issue, splenocytes from uninfected mice were incubated for 4 h with or without recombinant IL-4. IL-4 inhibited VIP mRNA expression. F4/80+ macrophages were the source of constitutively expressed VIP, subject to IL-4 regulation. In IL-4 knockout mice, splenic VIP production did not downmodulate during schistosome infection, suggesting that IL-4 is a critical cytokine regulating VIP production in wild-type mouse spleen. IL-4-producing granulomas in schistosomiasis made VIP. Experiments showed that granuloma VIP derived from F4/80- (nonmacrophage) cell populations, explaining this paradox. Granuloma F4/80+ cells from IL-4 knockout mice expressed VIP. Thus macrophages can make VIP, which is subject to IL-4 regulation. However, in the Th2 granulomas, other cell types produce VIP, which compensates for loss of macrophages as a source of this molecule.
Metwali
Ahmed
A
Division of Gastroenterology-Hepatology, Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
Blum
Arthur M
AM
Elliott
David E
DE
Weinstock
Joel V
JV
D000818:Animals; D002478:Cells, Cultured; D006099:Granuloma / Q000378:metabolism / Q000469:parasitology; D015847:Interleukin-4 / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012016:Reference Values; D012555:Schistosomiasis mansoni / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D014660:Vasoactive Intestinal Peptide / Q000037:antagonists & inhibitors* / Q000378:metabolism
D011498:Protein Precursors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D015847:Interleukin-4; D014660:Vasoactive Intestinal Peptide; C055594:preprovasoactive intestinal peptide