Abstract
BackgroundDiarrhea is a severe complication in HIV-1-infected patients with Trans-activator of transcription (HIV-1 Tat) protein being recognized as a major underlying cause. Beside its direct enterotoxic effects, Tat protein has been recently shown to affect enteric glial cell (EGC) activity. EGCs regulate intestinal inflammatory responses by secreting pro-inflammatory molecules; nonetheless, they might also release immune-regulatory factors, as palmytoilethanolamide (PEA), which exerts anti-inflammatory effects by activating PPARα receptors. We aimed at clarifying whether EGCs are involved in HIV-1 Tat-induced diarrhea and if PEA exerts antidiarrheal activity.MethodsDiarrhea was induced by intracolonic administration of HIV-1 Tat protein in rats at day 1. PEA alone or in the presence of peroxisome proliferator-activated receptor (PPAR) antagonists was given intraperitoneally from day 2 to day 7. S100B, iNOS, NF-kappaB, TLR4 and GFAP expression were evaluated in submucosal plexi, while S100B and NO levels were measured in EGC submucosal plexi lysates, respectively. To verify whether PEA effects were PPARα-mediated, PPARα−/− mice were also used. After 7 days from diarrhea induction, endogenous PEA levels were measured in submucosal plexi homogenates deriving from rats and PPARα−/− mice.ResultsHIV-1 Tat protein induced rapid onset diarrhea alongside with a significant activation of EGCs. Tat administration significantly increased all hallmarks of neuroinflammation by triggering TLR4 and NF-kappaB activation and S100B and iNOS expression. Endogenous PEA levels were increased following HIV-1 Tat exposure in both wildtype and knockout animals. In PPARα−/− mice, PEA displayed no effects. In wildtype rats, PEA, via PPARα-dependent mechanism, resulted in a significant antidiarrheal activity in parallel with marked reduction of EGC-sustained neuroinflammation.ConclusionsEGCs mediate HIV-1 Tat-induced diarrhea by sustaining the intestinal neuroinflammatory response. These effects are regulated by PEA through a selective PPARα-dependent mechanism. PEA might be considered as an adjuvant therapy in HIV-1-induced diarrhea.
Highlights
Diarrhea is a severe complication in human immunodeficiency virus-type 1 (HIV-1)-infected patients with Trans-activator of transcription (HIV-1 trans-activating factor protein (Tat)) protein being recognized as a major underlying cause
We found that HIV-1 Tat significantly increased the levels of endogenous PEA and that this increase was significantly inhibited by lidocaine (+ 147 and − 50% vs. vehicle group and HIV-1 Tat group, respectively; all p < 0.01; Fig. 2); in rats receiving bisacodyl, the tissue content of PEA was unaffected, likely suggesting that it is dependent by the activation of enteric glial cells (EGCs)
HIV-1 Tat induces an inflammatory response through EGC activation that is inhibited by PEA Administration of HIV-1 Tat induced a significant activation of NF-κΒ and resulted in an increased expression of Glial fibrillary acidic protein (GFAP), S100B, Toll-like receptor 4 (TLR4), and isoform of nitric oxide synthase (iNOS) in rat submucosal plexi (Fig. 3, all p < 0.001 vs. vehicle group); significantly, the S100B and nitrite levels were increased
Summary
Diarrhea is a severe complication in HIV-1-infected patients with Trans-activator of transcription (HIV-1 Tat) protein being recognized as a major underlying cause. Beside its direct enterotoxic effects, Tat protein has been recently shown to affect enteric glial cell (EGC) activity. EGCs regulate intestinal inflammatory responses by secreting pro-inflammatory molecules; they might release immune-regulatory factors, as palmytoilethanolamide (PEA), which exerts anti-inflammatory effects by activating PPARα receptors. HIV-1 Tat targets enterocytes and induces the expression of many genes regulating cells’ survival and growth; but it affects immune and inflammatory responses, altering the intracellular calcium concentration, inducing epithelial cell apoptosis, and causing secretory diarrhea [5, 6]. Among EGC-derived factors, S100B, a specific glial Ca+ 2/Zn+ 2-binding protein, and nitric oxide (NO) deriving from the inducible isoform of nitric oxide synthase (iNOS) expressed by EGCs play a central role during immune-inflammatory responses [14, 19, 20]. We recently demonstrated that glial cells participate to HIV-1 Tat-induced intestinal and neurological pathogenesis [21], but the possibility to pharmacologically modulate Tatinduced secretory diarrhea by inhibiting EGC activation has not been explored yet
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