PMID- 29138532 OWN - NLM STAT- MEDLINE DCOM- 20180702 LR - 20190116 IS - 1466-1861 (Electronic) IS - 0962-9351 (Print) IS - 0962-9351 (Linking) VI - 2017 DP - 2017 TI - Ubiquitin-Specific Protease 2 Modulates the Lipopolysaccharide-Elicited Expression of Proinflammatory Cytokines in Macrophage-like HL-60 Cells. PG - 6909415 LID - 10.1155/2017/6909415 [doi] LID - 6909415 AB - We investigated the regulatory roles of USP2 in mRNA accumulation of proinflammatory cytokines in macrophage-like cells after stimulation with a toll-like receptor (TLR) 4 ligand, lipopolysaccharide (LPS). Human macrophage-like HL-60 cells, mouse macrophage-like J774.1 cells, and mouse peritoneal macrophages demonstrated negative feedback to USP2 mRNA levels after LPS stimulation, suggesting that USP2 plays a significant role in LPS-stimulated macrophages. USP2 knockdown (KD) by short hairpin RNA in HL-60 cells promoted the accumulation of transcripts for 25 of 104 cytokines after LPS stimulation. In contrast, limited induction of cytokines was observed in cells forcibly expressing the longer splice variant of USP2 (USP2A), or in peritoneal macrophages isolated from Usp2a transgenic mice. An ubiquitin isopeptidase-deficient USP2A mutant failed to suppress LPS-induced cytokine expression, suggesting that protein ubiquitination contributes to USP2-mediated cytokine repression. Although USP2 deficiency did not accelerate TNF receptor-associated factor (TRAF) 6-nuclear factor-kappaB (NF-kappaB) signaling, it increased the DNA binding ratio of the octamer binding transcription factor (Oct)-1 to Oct-2 in TNF, CXCL8, CCL4, and IL6 promoters. USP2 decreased nuclear Oct-2 protein levels in addition to decreasing the polyubiquitination of Oct-1. In summary, USP2 modulates proinflammatory cytokine induction, possibly through modification of Oct proteins, in macrophages following TLR4 activation. FAU - Kitamura, Hiroshi AU - Kitamura H AUID- ORCID: 0000-0001-9643-3211 AD - Laboratory of Veterinary Physiology, Department of Veterinary Medicine, School of Veterinary Medicine, Rakuno Gakuen University, 582 Bunkyodai-Midorimachi, Ebetsu, Hokkaido 069-8501, Japan. AD - Department of Comparative and Experimental Medicine, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Aichi, Japan. FAU - Ishino, Takeshi AU - Ishino T AUID- ORCID: 0000-0001-6714-4242 AD - Laboratory of Veterinary Physiology, Department of Veterinary Medicine, School of Veterinary Medicine, Rakuno Gakuen University, 582 Bunkyodai-Midorimachi, Ebetsu, Hokkaido 069-8501, Japan. FAU - Shimamoto, Yoshinori AU - Shimamoto Y AUID- ORCID: 0000-0002-4212-498X AD - Laboratory of Animal Therapeutics, Department of Veterinary Science, Rakuno Gakuen University, 582 Bunkyodai-Midorimachi, Ebetsu, Hokkaido 069-8501, Japan. FAU - Okabe, Jun AU - Okabe J AUID- ORCID: 0000-0002-7196-0522 AD - Department of Diabetes, Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, 99 Commercial Road, Melbourne, VIC 3004, Australia. FAU - Miyamoto, Tomomi AU - Miyamoto T AD - Department of Comparative and Experimental Medicine, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Aichi, Japan. FAU - Takahashi, Eiki AU - Takahashi E AD - Research Resources Center, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama, Japan. FAU - Miyoshi, Ichiro AU - Miyoshi I AUID- ORCID: 0000-0001-6578-3390 AD - Department of Comparative and Experimental Medicine, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Aichi, Japan. LA - eng PT - Journal Article DEP - 20170912 PL - United States TA - Mediators Inflamm JT - Mediators of inflammation JID - 9209001 RN - 0 (Cytokines) RN - 0 (Drosophila Proteins) RN - 0 (Interleukin-6) RN - 0 (Lipopolysaccharides) RN - 0 (NF-kappa B) RN - 0 (RNA, Messenger) RN - 0 (TLR4 protein, human) RN - 0 (Toll-Like Receptor 4) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 3.4.19.12 (USP2 protein, Drosophila) RN - EC 3.4.19.12 (Ubiquitin-Specific Proteases) SB - IM MH - Animals MH - Cell Line MH - Cytokines/metabolism MH - Drosophila Proteins/*metabolism MH - HL-60 Cells MH - Humans MH - Interleukin-6/metabolism MH - Lipopolysaccharides/pharmacology MH - Macrophages/drug effects/metabolism MH - Mice MH - NF-kappa B/metabolism MH - RNA, Messenger/metabolism MH - Signal Transduction/drug effects MH - Toll-Like Receptor 4/metabolism MH - Tumor Necrosis Factor-alpha/metabolism MH - Ubiquitin-Specific Proteases/*metabolism PMC - PMC5613470 EDAT- 2017/11/16 06:00 MHDA- 2018/07/03 06:00 PMCR- 2017/09/12 CRDT- 2017/11/16 06:00 PHST- 2017/06/02 00:00 [received] PHST- 2017/07/21 00:00 [revised] PHST- 2017/07/30 00:00 [accepted] PHST- 2017/11/16 06:00 [entrez] PHST- 2017/11/16 06:00 [pubmed] PHST- 2018/07/03 06:00 [medline] PHST- 2017/09/12 00:00 [pmc-release] AID - 10.1155/2017/6909415 [doi] PST - ppublish SO - Mediators Inflamm. 2017;2017:6909415. doi: 10.1155/2017/6909415. Epub 2017 Sep 12.