Prostaglandin signaling (Homo sapiens)

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23598132428103020241216, 29Gene/ProteinFibroblastsNK cellsLegendProtection against viral infectionDecreased recruitment of CCR2 expressing monocytes and macrophagesDecreased platelet activationHuman Plasmacytoid Dendritic Cellspro-IL1BcAMPIRF7Ca2+ effluxProstaglandin E2 receptorProstaglandin E2Prostaglandin E receptor 4IFNA1VEGFAIL6Prostaglandin E receptor 4CSF1IL6IL8COX2Prostaglandin E2MMP9IL17AIL6IL8IL1BMonocytes, macrophages, fibroblasts, airway epithelial cellsTh17 cellsProstaglandin E2 receptorCCL2CXCL1MacrophageAREGVEGFATGFB1M2 MacrophageTissue repair, potential lung fibrosisProstaglandin E2 receptorProstaglandin E receptor 4NET formationProstaglandin E2 receptorProstaglandin E receptor 4PKAT cell activation and proliferationTh17 cellsIL17AIL17FAHR Inflammatory Th17 cell expansion17IFNGIL12AProstaglandin E receptor 4Natural killer cells antigen CD94NK and CD8+ T cell cytolytic activity4, 23CXCL9CXCL10NK cell migration719815, 18cAMPcAMPNFKB1Cytokine storm, hyperinflammation (postive feedback loop)IL1BProstaglandin I2IFNA1IL1BIL6TNF1TNFCCL26Th17 cells27Th1 cellsIL17AIFNGIP-activated cAMP22IFN SignalingProstaglandin E synthaseCOX2Prostaglandin E2IL6IL8TNFIL1ACCL2CXCL10CCL3IL1BNF-κB signalingEpithelial cells, monocytes, macrophages21FibroblastsProstaglandin E receptor 4Prostaglandin E2 receptor11, 14, 2526IL6 SignalingASCNLRP3pro-CASP1Macrophages and monocytesInflammasome ActivationCCR2Monocytes and neutrophilsMonocyte and Macrophage FunctionsNeutrophil Extracellular Trap (NET) ReleasePI3K24CD28T Cell Function17Myeloid cellsNK Cell FunctionsT Cell ResponsesCASP1MetaboliteComplexActivationStimulationConversionInhibition


This pathway describes elements of Prostaglandin signaling in Homo sapiens affected by COVID-19. Prostaglandins are amongst the many inflammatory mediators that incite a cytokine storm in COVID-19 after Bradykinin receptor B1 (BDKRB1) activation. This pathway mainly focuses on PGE2 and PGI2 and their interactions that lead to hyperinflammation via cytokine storms, immunothrombosis as well as the recruitment of fibrosis-mediating factors (VEGF, TGFB1, AREG). These pathways take place in multiple cell types such as: Monocytes, Macrophages, Fibroblasts, Th17 cells, Nk cells, et cetera.

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  1. Honda T, Segi-Nishida E, Miyachi Y, Narumiya S; ''Prostacyclin-IP signaling and prostaglandin E2-EP2/EP4 signaling both mediate joint inflammation in mouse collagen-induced arthritis.''; J Exp Med, 2006 PubMed Europe PMC Scholia
  2. Shishikura K, Horiuchi T, Sakata N, Trinh DA, Shirakawa R, Kimura T, Asada Y, Horiuchi H; ''Prostaglandin E2 inhibits neutrophil extracellular trap formation through production of cyclic AMP.''; Br J Pharmacol, 2016 PubMed Europe PMC Scholia
  3. Fabricius D, Neubauer M, Mandel B, Schütz C, Viardot A, Vollmer A, Jahrsdörfer B, Debatin KM; ''Prostaglandin E2 inhibits IFN-alpha secretion and Th1 costimulation by human plasmacytoid dendritic cells via E-prostanoid 2 and E-prostanoid 4 receptor engagement.''; J Immunol, 2010 PubMed Europe PMC Scholia
  4. ''''; , PubMed Europe PMC Scholia
  5. Robb CT, Goepp M, Rossi AG, Yao C; ''Non-steroidal anti-inflammatory drugs, prostaglandins, and COVID-19.''; Br J Pharmacol, 2020 PubMed Europe PMC Scholia
  6. Zhou W, Dowell DR, Huckabee MM, Newcomb DC, Boswell MG, Goleniewska K, Lotz MT, Toki S, Yin H, Yao S, Natarajan C, Wu P, Sriram S, Breyer RM, Fitzgerald GA, Peebles RS Jr; ''Prostaglandin I2 signaling drives Th17 differentiation and exacerbates experimental autoimmune encephalomyelitis.''; PLoS One, 2012 PubMed Europe PMC Scholia
  7. Van Elssen CH, Vanderlocht J, Oth T, Senden-Gijsbers BL, Germeraad WT, Bos GM; ''Inflammation-restraining effects of prostaglandin E2 on natural killer-dendritic cell (NK-DC) interaction are imprinted during DC maturation.''; Blood, 2011 PubMed Europe PMC Scholia
  8. Yao C, Narumiya S; ''Prostaglandin-cytokine crosstalk in chronic inflammation.''; Br J Pharmacol, 2019 PubMed Europe PMC Scholia
  9. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; ''COVID-19: consider cytokine storm syndromes and immunosuppression.''; Lancet, 2020 PubMed Europe PMC Scholia
  10. Siu KL, Yuen KS, Castaño-Rodriguez C, Ye ZW, Yeung ML, Fung SY, Yuan S, Chan CP, Yuen KY, Enjuanes L, Jin DY; ''Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC.''; FASEB J, 2019 PubMed Europe PMC Scholia
  11. Chen BC, Liao CC, Hsu MJ, Liao YT, Lin CC, Sheu JR, Lin CH; ''Peptidoglycan-induced IL-6 production in RAW 264.7 macrophages is mediated by cyclooxygenase-2, PGE2/PGE4 receptors, protein kinase A, I kappa B kinase, and NF-kappa B.''; J Immunol, 2006 PubMed Europe PMC Scholia
  12. Wynn TA, Vannella KM; ''Macrophages in Tissue Repair, Regeneration, and Fibrosis.''; Immunity, 2016 PubMed Europe PMC Scholia
  13. Robb CT, McSorley HJ, Lee J, Aoki T, Yu C, Crittenden S, Astier A, Felton JM, Parkinson N, Ayele A, Breyer RM, Anderton SM, Narumiya S, Rossi AG, Howie SE, Guttman-Yassky E, Weller RB, Yao C; ''Prostaglandin E2stimulates adaptive IL-22 production and promotes allergic contact dermatitis.''; J Allergy Clin Immunol, 2018 PubMed Europe PMC Scholia
  14. Li T, Qi J, Cowley EA; ''Activation of the EP₄ prostanoid receptor induces prostaglandin E₂ and pro-inflammatory cytokine production in human airway epithelial cells.''; Pulm Pharmacol Ther, 2011 PubMed Europe PMC Scholia
  15. Boniface K, Bak-Jensen KS, Li Y, Blumenschein WM, McGeachy MJ, McClanahan TK, McKenzie BS, Kastelein RA, Cua DJ, de Waal Malefyt R; ''Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling.''; J Exp Med, 2009 PubMed Europe PMC Scholia
  16. Liao M, Liu Y, Yuan J, Wen Y, Xu G, Zhao J, Cheng L, Li J, Wang X, Wang F, Liu L, Amit I, Zhang S, Zhang Z; ''Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19.''; Nat Med, 2020 PubMed Europe PMC Scholia
  17. Zhou Z, Ren L, Zhang L, Zhong J, Xiao Y, Jia Z, Guo L, Yang J, Wang C, Jiang S, Yang D, Zhang G, Li H, Chen F, Xu Y, Chen M, Gao Z, Dong J, Liu B, Zhang X, Wang W, He K, Jin Q, Li M, Wang J; ''Heightened Innate Immune Responses in the Respiratory Tract of COVID-19 Patients.''; Cell Host Microbe, 2020 PubMed Europe PMC Scholia
  18. Lee J, Aoki T, Thumkeo D, Siriwach R, Yao C, Narumiya S; ''T cell-intrinsic prostaglandin E2-EP2/EP4 signaling is critical in pathogenic TH17 cell-driven inflammation.''; J Allergy Clin Immunol, 2019 PubMed Europe PMC Scholia
  19. Gustafsson K, Junevik K, Werlenius O, Holmgren S, Karlsson-Parra A, Andersson PO; ''Tumour-loaded α-type 1-polarized dendritic cells from patients with chronic lymphocytic leukaemia produce a superior NK-, NKT- and CD8+ T cell-attracting chemokine profile.''; Scand J Immunol, 2011 PubMed Europe PMC Scholia
  20. Hashimoto K, Graham BS, Geraci MW, FitzGerald GA, Egan K, Zhou W, Goleniewska K, O'Neal JF, Morrow JD, Durbin RK, Wright PF, Collins RD, Suzutani T, Peebles RS Jr; ''Signaling through the prostaglandin I2 receptor IP protects against respiratory syncytial virus-induced illness.''; J Virol, 2004 PubMed Europe PMC Scholia
  21. Paulissen SM, van Hamburg JP, Davelaar N, Asmawidjaja PS, Hazes JM, Lubberts E; ''Synovial fibroblasts directly induce Th17 pathogenicity via the cyclooxygenase/prostaglandin E2 pathway, independent of IL-23.''; J Immunol, 2013 PubMed Europe PMC Scholia
  22. Inoue H, Takamori M, Shimoyama Y, Ishibashi H, Yamamoto S, Koshihara Y; ''Regulation by PGE2 of the production of interleukin-6, macrophage colony stimulating factor, and vascular endothelial growth factor in human synovial fibroblasts.''; Br J Pharmacol, 2002 PubMed Europe PMC Scholia
  23. Zeddou M, Greimers R, de Valensart N, Nayjib B, Tasken K, Boniver J, Moutschen M, Rahmouni S; ''Prostaglandin E2 induces the expression of functional inhibitory CD94/NKG2A receptors in human CD8+ T lymphocytes bya cAMP-dependent protein kinase A type I pathway.''; Biochem Pharmacol, 2005 PubMed Europe PMC Scholia
  24. Yao C, Hirata T, Soontrapa K, Ma X, Takemori H, Narumiya S; ''Prostaglandin E₂ promotes Th1 differentiation via synergistic amplification of IL-12 signalling by cAMP and PI3-kinase.''; Nat Commun, 2013 PubMed Europe PMC Scholia
  25. Cho JS, Han IH, Lee HR, Lee HM; ''Prostaglandin E2 Induces IL-6 and IL-8 Production by the EP Receptors/Akt/NF-κB Pathways in Nasal Polyp-Derived Fibroblasts.''; Allergy Asthma Immunol Res, 2014 PubMed Europe PMC Scholia
  26. Kothari P, Pestana R, Mesraoua R, Elchaki R, Khan KM, Dannenberg AJ, Falcone DJ; ''IL-6-mediated induction of matrix metalloproteinase-9 is modulated by JAK-dependent IL-10 expression in macrophages.''; J Immunol, 2014 PubMed Europe PMC Scholia
  27. Nakajima S, Honda T, Sakata D, Egawa G, Tanizaki H, Otsuka A, Moniaga CS, Watanabe T, Miyachi Y, Narumiya S, Kabashima K; ''Prostaglandin I2-IP signaling promotes Th1 differentiation in a mouse model of contact hypersensitivity.''; J Immunol, 2010 PubMed Europe PMC Scholia
  28. Zasłona Z, Pålsson-McDermott EM, Menon D, Haneklaus M, Flis E, Prendeville H, Corcoran SE, Peters-Golden M, O'Neill LAJ; ''The Induction of Pro-IL-1β by Lipopolysaccharide Requires Endogenous Prostaglandin E2Production.''; J Immunol, 2017 PubMed Europe PMC Scholia
  29. Xiong Y, Liu Y, Cao L, Wang D, Guo M, Jiang A, Guo D, Hu W, Yang J, Tang Z, Wu H, Lin Y, Zhang M, Zhang Q, Shi M, Zhou Y, Lan K, Chen Y; ''Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients.''; Emerg Microbes Infect, 2020 PubMed Europe PMC Scholia
  30. Kumei S, Yuhki KI, Kojima F, Kashiwagi H, Imamichi Y, Okumura T, Narumiya S, Ushikubi F; ''Prostaglandin I2suppresses the development of diet-induced nonalcoholic steatohepatitis in mice.''; FASEB J, 2018 PubMed Europe PMC Scholia


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119639view06:34, 27 July 2021EgonwNot a conversion
119319view13:32, 23 June 2021AriajadhavUpdated and restructured pathway. Added legend
119018view19:19, 9 June 2021EgonwNot a human gene id
118971view12:33, 5 June 2021EgonwNot a human gene ID
117086view20:38, 16 May 2021AriajadhavMade the pathway compact
116865view14:51, 14 May 2021AriajadhavConnected lines
116773view00:28, 14 May 2021AriajadhavUpdated pathway, added references
116698view18:38, 9 May 2021AriajadhavModified description
116418view09:09, 7 May 2021EweitzModified title
116320view11:27, 30 April 2021Marvin M2Ontology Term : 'prostaglandin I2 signaling pathway' added !
116319view11:25, 30 April 2021Marvin M2Ontology Term : 'prostaglandin E2 signaling pathway' added !
116318view11:25, 30 April 2021Marvin M2Ontology Term : 'COVID-19' added !
116317view11:23, 30 April 2021Marvin M2connected lines
116312view15:10, 29 April 2021AriajadhavNew pathway

External references


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NameTypeDatabase referenceComment
AHR ProteinENSG00000106546 (Ensembl)
AREGGeneProductENSG00000109321 (Ensembl)
ASCGeneProductENSG00000103490 (Ensembl)
CASP1GeneProductENSG00000137752 (Ensembl)
CCL2GeneProductENSG00000108691 (Ensembl)
CCL3GeneProductENSG00000277632 (Ensembl)
CCR2GeneProductENSG00000121807 (Ensembl)
CD28GeneProductENSG00000178562 (Ensembl)
CSF1GeneProductENSG00000184371 (Ensembl)
CXCL10GeneProductENSG00000169245 (Ensembl)
CXCL1GeneProductENSG00000163739 (Ensembl)
CXCL9GeneProductENSG00000138755 (Ensembl)
Ca2+ effluxMetaboliteCHEBI:29108 (ChEBI)
IFNA1GeneProductENSG00000197919 (Ensembl)
IL12AGeneProductENSG00000168811 (Ensembl)
IL17AGeneProductENSG00000112115 (Ensembl)
IL17FGeneProductENSG00000112116 (Ensembl)
IL1AGeneProductENSG00000115008 (Ensembl)
IL1BGeneProductENSG00000125538 (Ensembl)
IL6GeneProductENSG00000136244 (Ensembl)
IL8 GeneProductENSG00000169429 (Ensembl)
IP-activated cAMPMetaboliteHMDB0000058 (HMDB)
IRF7GeneProductENSG00000185507 (Ensembl)
MMP9GeneProductENSG00000100985 (Ensembl)
NFKB1GeneProductENSG00000109320 (Ensembl)
NLRP3GeneProductENSG00000162711 (Ensembl)
Natural killer cells antigen CD94ProteinE9PCX9 (Uniprot-TrEMBL)
PI3KGeneProductENSG00000105851 (Ensembl)
PKAProteinEC (KEGG Genes)
Prostaglandin E receptor 4ProteinENSG00000171522 (Ensembl)
Prostaglandin E synthaseProteinO14684 (Uniprot-TrEMBL)
Prostaglandin E2 receptorProteinG3V2Y6 (Uniprot-TrEMBL)
Prostaglandin E2 receptorProteinP43116 (Uniprot-TrEMBL)
Prostaglandin E2Metabolite363-24-6 (CAS)
Prostaglandin I2Metabolite35121-78-9 (CAS)
TGFB1GeneProductTGFB1 (HGNC)
TNFGeneProductENSG00000232810 (Ensembl)
VEGFAGeneProductENSG00000112715 (Ensembl)
cAMPMetaboliteHMDB0000058 (HMDB)
pro-CASP1GeneProductENSG00000137752 (Ensembl)
pro-IL1BGeneProductENSG00000125538 (Ensembl)

Annotated Interactions

No annotated interactions

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