HIV-1 Tat-induced diarrhea is improved by the PPARalpha agonist, palmitoylethanolamide, by suppressing the activation of enteric glia
Abstract Background 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) activ...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2018-03-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-018-1126-4 |
| _version_ | 1811215073043021824 |
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| author | Giovanni Sarnelli Luisa Seguella Marcella Pesce Jie Lu Stefano Gigli Eugenia Bruzzese Roberta Lattanzi Alessandra D’Alessandro Rosario Cuomo Luca Steardo Giuseppe Esposito |
| author_facet | Giovanni Sarnelli Luisa Seguella Marcella Pesce Jie Lu Stefano Gigli Eugenia Bruzzese Roberta Lattanzi Alessandra D’Alessandro Rosario Cuomo Luca Steardo Giuseppe Esposito |
| author_sort | Giovanni Sarnelli |
| collection | DOAJ |
| description | Abstract Background 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; 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. Methods Diarrhea 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. Results HIV-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. Conclusions EGCs 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. |
| first_indexed | 2024-04-12T06:15:15Z |
| format | Article |
| id | doaj.art-c37e95a9d4a44e36a7d81fb3643a282a |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-12T06:15:15Z |
| publishDate | 2018-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-c37e95a9d4a44e36a7d81fb3643a282a2022-12-22T03:44:31ZengBMCJournal of Neuroinflammation1742-20942018-03-0115111010.1186/s12974-018-1126-4HIV-1 Tat-induced diarrhea is improved by the PPARalpha agonist, palmitoylethanolamide, by suppressing the activation of enteric gliaGiovanni Sarnelli0Luisa Seguella1Marcella Pesce2Jie Lu3Stefano Gigli4Eugenia Bruzzese5Roberta Lattanzi6Alessandra D’Alessandro7Rosario Cuomo8Luca Steardo9Giuseppe Esposito10Department of Clinical Medicine and Surgery, “Federico II” University of NaplesDepartment of Physiology and Pharmacology, “Vittorio Erspamer”, La Sapienza University of RomeDepartment of Clinical Medicine and Surgery, “Federico II” University of NaplesDepartment of Anatomy, China Medical UniversityDepartment of Physiology and Pharmacology, “Vittorio Erspamer”, La Sapienza University of RomeDepartment of Translational Medical Science, Section of Pediatrics, University Federico IIDepartment of Physiology and Pharmacology, “Vittorio Erspamer”, La Sapienza University of RomeDepartment of Clinical Medicine and Surgery, “Federico II” University of NaplesDepartment of Clinical Medicine and Surgery, “Federico II” University of NaplesDepartment of Clinical Medicine and Surgery, “Federico II” University of NaplesDepartment of Physiology and Pharmacology, “Vittorio Erspamer”, La Sapienza University of RomeAbstract Background 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; 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. Methods Diarrhea 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. Results HIV-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. Conclusions EGCs 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.http://link.springer.com/article/10.1186/s12974-018-1126-4HIV-1 Tat proteinEGCsDiarrheaNeuroinflammationPEA |
| spellingShingle | Giovanni Sarnelli Luisa Seguella Marcella Pesce Jie Lu Stefano Gigli Eugenia Bruzzese Roberta Lattanzi Alessandra D’Alessandro Rosario Cuomo Luca Steardo Giuseppe Esposito HIV-1 Tat-induced diarrhea is improved by the PPARalpha agonist, palmitoylethanolamide, by suppressing the activation of enteric glia Journal of Neuroinflammation HIV-1 Tat protein EGCs Diarrhea Neuroinflammation PEA |
| title | HIV-1 Tat-induced diarrhea is improved by the PPARalpha agonist, palmitoylethanolamide, by suppressing the activation of enteric glia |
| title_full | HIV-1 Tat-induced diarrhea is improved by the PPARalpha agonist, palmitoylethanolamide, by suppressing the activation of enteric glia |
| title_fullStr | HIV-1 Tat-induced diarrhea is improved by the PPARalpha agonist, palmitoylethanolamide, by suppressing the activation of enteric glia |
| title_full_unstemmed | HIV-1 Tat-induced diarrhea is improved by the PPARalpha agonist, palmitoylethanolamide, by suppressing the activation of enteric glia |
| title_short | HIV-1 Tat-induced diarrhea is improved by the PPARalpha agonist, palmitoylethanolamide, by suppressing the activation of enteric glia |
| title_sort | hiv 1 tat induced diarrhea is improved by the pparalpha agonist palmitoylethanolamide by suppressing the activation of enteric glia |
| topic | HIV-1 Tat protein EGCs Diarrhea Neuroinflammation PEA |
| url | http://link.springer.com/article/10.1186/s12974-018-1126-4 |
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