title: Proviral integration site 2 is required for interleukin-6 expression induced by interleukin-1, tumour necrosis factor-α and lipopolysaccharide.
abstract: PIM (proviral integration site) kinases are a distinct class of serine/threonine-specific kinases consisting of PIM1, PIM2 and PIM3. PIM2 is known to function in apoptosis pathways. Expression of PIM2 is highly induced by pro-inflammatory stimuli but the role of PIM2 in the expression of pro-inflammatory cytokines is unclear. In this study, we showed that over-expression of PIM2 in HeLa cells as well as in human umbilical vein endothelial cells enhanced interleukin-1β (IL-1β) -induced and tumour necrosis factor-α-induced IL-6 expression, whereas over-expression of a kinase-dead PIM2 mutant had the opposite effect. Studies with small interfering RNA specific to PIM2 further confirmed that IL-6 expression in HeLa cells requires PIM2. To investigate the function of PIM2 further, we generated PIM2-deficient mice. It was found that IL-6 production was significantly decreased from PIM2-deficient spleen cells after stimulation with lipopolysaccharide. Taken together, we demonstrated an important function of PIM2 in controlling the expression of the pro-inflammatory cytokine IL-6. PIM2 inhibitors may be beneficial for IL-6-mediated diseases such as rheumatoid arthritis.
authors.affiliation: Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT 06877, USA. jianfeiy@yahoo.com
authors.forename: Jianfei
authors.initials: J
authors.lastname: Yang
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Adedayo
authors.initials: A
authors.lastname: Hanidu
authors.forename: Tin M
authors.initials: TM
authors.lastname: Htut
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Sellati
authors.forename: Lian
authors.initials: L
authors.lastname: Wang
authors.forename: Huiping
authors.initials: H
authors.lastname: Jiang
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology*
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; C490587:PIM2 protein, human; C094167:Pim2 protein, mouse; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D017346:Protein Serine-Threonine Kinases
references.citation: Eur J Immunol. 1988 Nov;18(11):1797-801
references.pmid: 2462501
references.citation: Cancer Res. 2004 Nov 15;64(22):8341-8
references.pmid: 15548703
references.citation: Nat Immunol. 2001 Feb;2(2):157-64
references.pmid: 11175814
references.citation: Nature. 2001 May 24;411(6836):494-8
references.pmid: 11373684
references.citation: Biotechniques. 1999 Jun;26(6):1150-6, 1158, 1160
references.pmid: 10376154
references.citation: Oncogene. 1997 Sep 4;15(10):1133-41
references.pmid: 9294606
references.citation: J Immunol. 2005 Sep 15;175(6):3463-8
references.pmid: 16148087
references.citation: Cell. 1989 Feb 24;56(4):673-82
references.pmid: 2537153
references.citation: J Biol Chem. 2001 May 25;276(21):18579-90
references.pmid: 11279141
references.citation: J Immunol. 2005 Nov 15;175(10):6580-8
references.pmid: 16272312
references.citation: Genes Dev. 2003 Aug 1;17(15):1841-54
references.pmid: 12869584
references.citation: Int J Biochem Cell Biol. 2005 Apr;37(4):726-30
references.pmid: 15694833
references.citation: Immunity. 1998 Nov;9(5):745-55
references.pmid: 9846495
references.citation: Eur J Immunol. 2008 May;38(5):1204-14
references.pmid: 18412165
references.citation: J Biol Chem. 2003 Nov 14;278(46):45358-67
references.pmid: 12954615
references.citation: Brain Res Brain Res Protoc. 2000 Apr;5(2):211-7
references.pmid: 10775843
references.citation: Nucleic Acids Res. 1993 Oct 11;21(20):4750-5
references.pmid: 8233823
references.citation: Arthritis Res Ther. 2006;8 Suppl 2:S3
references.pmid: 16899107
references.citation: Arthritis Res Ther. 2006;8 Suppl 2:S5
references.pmid: 16899109
references.citation: EMBO J. 1985 Jul;4(7):1793-8
references.pmid: 2992942
references.citation: Eur J Immunol. 2006 Dec;36(12):3305-14
references.pmid: 17111354
references.citation: J Exp Med. 2005 Jan 17;201(2):259-66
references.pmid: 15642745
references.citation: J Leukoc Biol. 2002 Aug;72(2):410-6
references.pmid: 12149433
references.citation: J Biochem. 2007 Mar;141(3):353-62
references.pmid: 17234686
references.citation: J Exp Med. 1998 Feb 16;187(4):461-8
references.pmid: 9463396
references.citation: Leuk Lymphoma. 2004 May;45(5):951-5
references.pmid: 15291354
references.citation: EMBO J. 1995 Jun 1;14(11):2536-44
references.pmid: 7781606
references.citation: J Immunol. 2004 May 15;172(10):5870-9
references.pmid: 15128766
references.citation: Mol Cell Biol. 2004 Jul;24(13):6104-15
references.pmid: 15199164
references.citation: Am J Respir Cell Mol Biol. 2002 Apr;26(4):465-74
references.pmid: 11919083
references.citation: Immunology. 2005 Sep;116(1):82-8
references.pmid: 16108820
references.citation: J Biol Chem. 2002 Nov 22;277(47):45129-40
references.pmid: 12221085
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):270-5
references.pmid: 17185414
references.citation: Virology. 2005 Mar 15;333(2):201-6
references.pmid: 15721354