IL-4 inhibits vasoactive intestinal peptide production by macrophages

Abstract

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.

The Significance of Vasoactive Intestinal Peptide in Immunomodulation

“…We did not find VIP-ir or VIP gene expression in macrophages from lymphoid organs and peritoneal suspensions Delgado et al, 1996d), whereas Metwali et al (2002) described production of VIP by macrophages. Differences in state of cell activation or macrophage source could explain the discrepancy.…”

“…On one hand, antigen-stimulated Th2 cells secrete VIP , which then promotes Th2 differentiation and survival, leading to more IL-4 production Delgado et al, 2002c). On the other hand, IL-4 inhibits constitutive VIP production by macrophages and reduces the levels of VPAC 2 receptors on Th2, but not Th1, cells (Metwali et al, 2000(Metwali et al, , 2002.…”

CD19, a Response Regulator of B Lymphocytes, Regulates Wound Healing through Hyaluronan-Induced TLR4 Signaling

“…19,20 Flow cytometric analysis confirmed the adequacy of the separation (Ͼ95%). Purified macrophages were cultured in 0.6 ml of serum-free RPMI medium in 48-well flat-bottom plates at 37°C for 8 hours with IL-6 (Acris antibodies, Hiddenhausen, Germany), IL-10 (Acris antibodies), or TGF-␤1 (R&D systems) at the indicated concentrations.…”

Differential expression pattern of pituitary adenylate cyclase-activating polypeptide (PACAP) alternative splicing variants and its receptors in the immune system of rainbow trout (Oncorhynchus mykiss)

“…Although PACAP expression in macrophages has not been described, studies concerning the expression of VIP (a close-related PACAP peptide) in macrophages have shown contradictory results. Some studies have been revealed the absence of the VIP expression in rat macrophages from lymphoid organs and in rat peritoneal macrophages [35,36], whereas, Metwalli and co-workers in 2002 reported the constitutively expression of VIP in splenic monocytes/macrophages subsets of healthy mice [37]. This inconsistency could be achieved to a dissimilar stage of activation or to the origin of the studied macrophages.…”