Pharmacological inhibitors of the mevalonate pathway activate pro-IL-1 processing and IL-1 release by human monocytes

The effects of statins (3-hydroxy-3-methylglutaryl coenzyme A reductase-HMGR-inhibitors) on the inflammatory response remain unclear. HMGR is implicated in the mevalonate pathway, directly upstream of cholesterol biosynthesis. We studied the impairment by this pathway of cytokine production by perip...

Full description

Saved in:
Bibliographic Details
Published inEuropean cytokine network Vol. 20; no. 3; p. 112
Main Authors Massonnet, Benoit, Normand, Sylvain, Moschitz, Reinhard, Delwail, Adriana, Favot, Laure, Garcia, Martine, Bourmeyster, Nicolas, Cuisset, Laurence, Grateau, Gilles, Morel, Franck, Silvain, Christine, Lecron, Jean-Claude
Format Journal Article
LanguageEnglish
Published France 01.09.2009
Subjects
Online AccessGet more information

Cover

Loading…
Abstract The effects of statins (3-hydroxy-3-methylglutaryl coenzyme A reductase-HMGR-inhibitors) on the inflammatory response remain unclear. HMGR is implicated in the mevalonate pathway, directly upstream of cholesterol biosynthesis. We studied the impairment by this pathway of cytokine production by peripheral blood mononuclear cells (PBMCs) and THP-1 cells. The aim was to identify a specific cytokine "signature" of cells under simvastatin treatment in order to link pharmacological inhibition of the mevalonate pathway and inflammation. Normal human PBMCs and THP-1 cells were cultured with inhibitors of HMGR (simvastatin), geranylgeranyltransferase (GGTI-298), farnesyltransferase (FTI-277), and/or caspase-1 (Z-VAD(Ome)-FMK). Following culture, cytokine production, caspase-1 activity, IL-1beta mRNA and Rac-1 activity were determined. Pharmacological inhibition of the mevalonate pathway specifically enhanced the release of IL-1alpha, IL-1beta and IL-18 and inhibited IL-1ra production by LPS-activated PBMCs and THP-1 cells. Simvastatin did not modify pro-IL-1beta expression, but enhanced caspase-1 activity, the enzyme responsible for IL-1beta and IL-18 maturation. GGTI-298 also enhanced IL-1-family cytokine production, showing that geranylgeranylation is involved in caspase-1 activation. Additionally, simvastatin enhanced Rac-1 activity. Pharmacological inhibition of the mevalonate pathway by statins highlighted the specific induction of the proinflammatory cytokines of the IL-1 family whose maturation is either directly (i.e. IL-1beta and IL-18), or indirectly (i.e. IL-1alpha) dependant on caspase-1.
AbstractList The effects of statins (3-hydroxy-3-methylglutaryl coenzyme A reductase-HMGR-inhibitors) on the inflammatory response remain unclear. HMGR is implicated in the mevalonate pathway, directly upstream of cholesterol biosynthesis. We studied the impairment by this pathway of cytokine production by peripheral blood mononuclear cells (PBMCs) and THP-1 cells. The aim was to identify a specific cytokine "signature" of cells under simvastatin treatment in order to link pharmacological inhibition of the mevalonate pathway and inflammation. Normal human PBMCs and THP-1 cells were cultured with inhibitors of HMGR (simvastatin), geranylgeranyltransferase (GGTI-298), farnesyltransferase (FTI-277), and/or caspase-1 (Z-VAD(Ome)-FMK). Following culture, cytokine production, caspase-1 activity, IL-1beta mRNA and Rac-1 activity were determined. Pharmacological inhibition of the mevalonate pathway specifically enhanced the release of IL-1alpha, IL-1beta and IL-18 and inhibited IL-1ra production by LPS-activated PBMCs and THP-1 cells. Simvastatin did not modify pro-IL-1beta expression, but enhanced caspase-1 activity, the enzyme responsible for IL-1beta and IL-18 maturation. GGTI-298 also enhanced IL-1-family cytokine production, showing that geranylgeranylation is involved in caspase-1 activation. Additionally, simvastatin enhanced Rac-1 activity. Pharmacological inhibition of the mevalonate pathway by statins highlighted the specific induction of the proinflammatory cytokines of the IL-1 family whose maturation is either directly (i.e. IL-1beta and IL-18), or indirectly (i.e. IL-1alpha) dependant on caspase-1.
Author Delwail, Adriana
Cuisset, Laurence
Bourmeyster, Nicolas
Silvain, Christine
Grateau, Gilles
Moschitz, Reinhard
Lecron, Jean-Claude
Favot, Laure
Morel, Franck
Massonnet, Benoit
Normand, Sylvain
Garcia, Martine
Author_xml – sequence: 1
  givenname: Benoit
  surname: Massonnet
  fullname: Massonnet, Benoit
  organization: Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, EA 4331, Université de Poitiers, Poitiers, France
– sequence: 2
  givenname: Sylvain
  surname: Normand
  fullname: Normand, Sylvain
– sequence: 3
  givenname: Reinhard
  surname: Moschitz
  fullname: Moschitz, Reinhard
– sequence: 4
  givenname: Adriana
  surname: Delwail
  fullname: Delwail, Adriana
– sequence: 5
  givenname: Laure
  surname: Favot
  fullname: Favot, Laure
– sequence: 6
  givenname: Martine
  surname: Garcia
  fullname: Garcia, Martine
– sequence: 7
  givenname: Nicolas
  surname: Bourmeyster
  fullname: Bourmeyster, Nicolas
– sequence: 8
  givenname: Laurence
  surname: Cuisset
  fullname: Cuisset, Laurence
– sequence: 9
  givenname: Gilles
  surname: Grateau
  fullname: Grateau, Gilles
– sequence: 10
  givenname: Franck
  surname: Morel
  fullname: Morel, Franck
– sequence: 11
  givenname: Christine
  surname: Silvain
  fullname: Silvain, Christine
– sequence: 12
  givenname: Jean-Claude
  surname: Lecron
  fullname: Lecron, Jean-Claude
BackLink https://www.ncbi.nlm.nih.gov/pubmed/19825520$$D View this record in MEDLINE/PubMed
BookMark eNo1j7FOwzAURS0EoqV0ZEX-gRTbie14RBWUSpVggLl6dl4aS4ldJU5R_h4oMN2rM5yre0MuQwxIyB1nK67K4gFdWAnGzIpxJS7InBspsoIxOSPLYfCWCS2ZlNpckxk3pZBSsDkZ3xroO3CxjQfvoKU-NN76FPuBxpqmBmmHJ2hjgIT0CKn5hImCS_50Bn3MtruM_xSH3zPhQCFU9Mx6bBEGpHaizdhBoF0M0U0Jh1tyVUM74PIvF-Tj-el9_ZLtXjfb9eMuc7kRKTO8UCYvLc-FszWwUnMEqQQDZThUuuaga1uKqgbnlCx4pUqjKqu4Rp1bIxbk_td7HG2H1f7Y-w76af__X3wBC9tezg
CitedBy_id crossref_primary_10_1021_acsomega_3c06389
crossref_primary_10_1016_j_bcp_2020_113862
crossref_primary_10_1007_s12265_013_9506_8
crossref_primary_10_18632_aging_203824
crossref_primary_10_1016_j_clim_2012_09_011
crossref_primary_10_1016_j_ymgme_2012_10_019
crossref_primary_10_1007_s10620_012_2217_1
crossref_primary_10_1016_j_biopha_2022_113304
crossref_primary_10_1038_s41419_019_2109_9
crossref_primary_10_1111_jnc_15113
crossref_primary_10_3389_fimmu_2019_01900
crossref_primary_10_3390_ijms24097818
crossref_primary_10_3390_jcm8111764
crossref_primary_10_3390_ijms25115856
crossref_primary_10_1016_j_cytogfr_2016_11_001
crossref_primary_10_1155_2018_3514645
crossref_primary_10_1164_rccm_201108_1574OC
crossref_primary_10_1038_icb_2016_58
crossref_primary_10_1007_s11825_012_0335_y
crossref_primary_10_20900_immunometab20210023
crossref_primary_10_1016_j_biopha_2023_115885
crossref_primary_10_3389_fimmu_2023_1301051
crossref_primary_10_1007_s12016_020_08791_9
crossref_primary_10_1074_jbc_M114_571505
crossref_primary_10_1016_j_biopha_2016_04_043
crossref_primary_10_3390_nu15061517
crossref_primary_10_1177_1074248418776261
crossref_primary_10_1172_JCI160929
ContentType Journal Article
DBID CGR
CUY
CVF
ECM
EIF
NPM
DOI 10.1684/ecn.2009.0162
DatabaseName Medline
MEDLINE
MEDLINE (Ovid)
MEDLINE
MEDLINE
PubMed
DatabaseTitle MEDLINE
Medline Complete
MEDLINE with Full Text
PubMed
MEDLINE (Ovid)
DatabaseTitleList MEDLINE
Database_xml – sequence: 1
  dbid: NPM
  name: PubMed
  url: https://proxy.k.utb.cz/login?url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed
  sourceTypes: Index Database
– sequence: 2
  dbid: EIF
  name: MEDLINE
  url: https://proxy.k.utb.cz/login?url=https://www.webofscience.com/wos/medline/basic-search
  sourceTypes: Index Database
DeliveryMethod no_fulltext_linktorsrc
EISSN 1952-4005
ExternalDocumentID 19825520
Genre Research Support, Non-U.S. Gov't
Journal Article
GroupedDBID AEBTG
AEPYU
ALFXC
ALMA_UNASSIGNED_HOLDINGS
CGR
CUY
CVF
ECM
EIF
NPM
ID FETCH-LOGICAL-c392t-9146938b132cbfa0871ea5620a691ad7f1a7fb82dfacc6541d6896db617e73b92
IngestDate Thu Nov 24 22:06:10 EST 2022
IsPeerReviewed true
IsScholarly true
Issue 3
Language English
LinkModel OpenURL
MergedId FETCHMERGED-LOGICAL-c392t-9146938b132cbfa0871ea5620a691ad7f1a7fb82dfacc6541d6896db617e73b92
PMID 19825520
ParticipantIDs pubmed_primary_19825520
PublicationCentury 2000
PublicationDate 2009-09-01
PublicationDateYYYYMMDD 2009-09-01
PublicationDate_xml – month: 09
  year: 2009
  text: 2009-09-01
  day: 01
PublicationDecade 2000
PublicationPlace France
PublicationPlace_xml – name: France
PublicationTitle European cytokine network
PublicationTitleAlternate Eur Cytokine Netw
PublicationYear 2009
SSID ssib027505579
Score 2.0550222
Snippet The effects of statins (3-hydroxy-3-methylglutaryl coenzyme A reductase-HMGR-inhibitors) on the inflammatory response remain unclear. HMGR is implicated in the...
SourceID pubmed
SourceType Index Database
StartPage 112
SubjectTerms Caspase 1 - metabolism
Cell Line
Enzyme Activation - drug effects
Guanosine Triphosphate - metabolism
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology
Interleukin-1 - secretion
Interleukin-1beta - secretion
Lipopolysaccharides - pharmacology
Metabolic Networks and Pathways - drug effects
Mevalonic Acid - metabolism
Monocytes - drug effects
Monocytes - enzymology
Monocytes - secretion
p38 Mitogen-Activated Protein Kinases - metabolism
Phosphorylation - drug effects
Protein Precursors - secretion
Protein Prenylation - drug effects
Protein Processing, Post-Translational - drug effects
Protein Transport - drug effects
rac1 GTP-Binding Protein - metabolism
Simvastatin - pharmacology
Title Pharmacological inhibitors of the mevalonate pathway activate pro-IL-1 processing and IL-1 release by human monocytes
URI https://www.ncbi.nlm.nih.gov/pubmed/19825520
Volume 20
hasFullText
inHoldings 1
isFullTextHit
isPrint
link http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV3LbtQwFLWmsGGDQDxbqLxghwJx4jjJskKgFtERi1bqrrIdW41okxFMW01_hx_l-JFkOjwEbKKRPWMl95yx7725D0JeCcuEyoVKQA4YKKbgCbQQnsgqrXWheKp9L4LDudg_5h9PipPZ7Pta1NLlUr3RN7_MK_kfVDEGXF2W7D8gOy6KAXwGvrgCYVz_CuPPU91pL-u2O2tV6_vnxFf_F66at3OQG1dB9exarnz1jCs_8LVPDj4l7PUiJAsM6Yp-zPVSwQHntNPQxg8P1evVMoYcbvryMdN_cQprF8LKJ0c3ROAyfzyPTNe3Y5jN3OcrBLf06vxKtiNND_tv7u3GTYAfDxUz_73Cbc6vZfBb7zUQcWj-PfotpsAsHDthr62LDOZrWqxvxlm6Rrp8bWdlIdr6px1fVNxhr7tYe5SJW98DYIsLDz-rYQwXYf0_z24U4B6mtshWWbnuIPPJIeSq4xdFWcfqrbiZt7duxdekDT_fsFu8_nL0gNyPhgfdCyx6SGame0QuNxhEJwbR3lIwiE4MopFBdGAQHRhEJwZRQEr9WGQQVSvqGURHBj0mxx_eH73bT2IjjkRDfV7iQOSizivF8kwrK1MY2UZCcU6lqJlsSstkaVWVNVZq7RrLN6KqRaOgHZsyV3X2hNzp-s48IzTl2lpeppxJaL6ikRoLS5DAws5Qkj8nT4OUTheh2srpIL_t387skHsTwV6QuxZ_b_MSuuJS7Xq0fgCCIm3G
link.rule.ids 780
linkProvider National Library of Medicine
openUrl ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Pharmacological+inhibitors+of+the+mevalonate+pathway+activate+pro-IL-1+processing+and+IL-1+release+by+human+monocytes&rft.jtitle=European+cytokine+network&rft.au=Massonnet%2C+Benoit&rft.au=Normand%2C+Sylvain&rft.au=Moschitz%2C+Reinhard&rft.au=Delwail%2C+Adriana&rft.date=2009-09-01&rft.eissn=1952-4005&rft.volume=20&rft.issue=3&rft.spage=112&rft_id=info:doi/10.1684%2Fecn.2009.0162&rft_id=info%3Apmid%2F19825520&rft_id=info%3Apmid%2F19825520&rft.externalDocID=19825520