PMID- 21835002
OWN - NLM
STAT- MEDLINE
DCOM- 20120329
LR  - 20211020
IS  - 1478-6362 (Electronic)
IS  - 1478-6354 (Print)
IS  - 1478-6354 (Linking)
VI  - 13
IP  - 4
DP  - 2011 Aug 11
TI  - Modulation of interleukin-1beta-induced inflammatory responses by a synthetic 
      cationic innate defence regulator peptide, IDR-1002, in synovial fibroblasts.
PG  - R129
LID - 10.1186/ar3440 [doi]
AB  - INTRODUCTION: Innate defence regulator (IDR) peptides are synthetic cationic 
      peptides, variants of naturally occurring innate immune effector molecules known 
      as host defence peptides. IDR peptides were recently demonstrated to limit 
      infection-associated inflammation selectively without compromising host innate 
      immune functions. This study examined the impact of a 12-amino acid IDR peptide, 
      IDR-1002, in pro-inflammatory cytokine interleukin (IL)-1beta-induced responses in 
      synovial fibroblasts, a critical cell type in the pathogenesis of inflammatory 
      arthritis. METHODS: Human fibroblast-like synoviocytes (FLS) were stimulated with 
      IL-1beta in the presence and absence of IDR-1002. Production of enzyme matrix 
      metalloproteinase-3 (MMP-3) and IL-1-receptor antagonist (IL-1RA) was monitored 
      by enzyme-linked immunosorbent assay (ELISA), and various chemokines were 
      evaluated by using multiplex cytometric bead array. Transcriptional responses 
      were analyzed by quantitative real-time PCR. The impact on IL-1beta-induced proteome 
      was investigated by quantitative proteomics by using isobaric tags. IL-1beta-induced 
      pathways altered by IDR-1002 implicated by the proteomics analyses were further 
      investigated by using various immunochemical assays. Cellular uptake of the 
      peptide was monitored by using a biotinylated IDR-1002 peptide followed by 
      microscopy probing with streptavidin-Alexa Fluor. RESULTS: This study 
      demonstrated that IDR-1002 suppressed the production of IL-1beta-induced MMP-3 and 
      monocyte chemotactic protein-1 (MCP-1); in contrast, IDR-1002 enhanced the 
      production of IL-1RA, without neutralizing all chemokine responses. IDR-1002 
      altered the IL-1beta-induced proteome primarily by altering the expression of 
      members of nuclear factor kappa-B (NF-kappaB) and c-Jun N-terminal kinase (JNK) 
      pathways. The proteomics data also suggested that IDR-1002 was altering the 
      transcription factor HNF-4alpha-mediated responses, known to be critical in metabolic 
      regulation. With various immunochemical assays, it was further demonstrated that 
      IL-1beta-induced NF-kappaB, JNK, and p38 mitogen-activated protein kinase (MAPK) 
      activations were significantly suppressed by IDR-1002. CONCLUSIONS: This study 
      demonstrates the ability of an innate immune-modulatory IDR-peptide to influence 
      the IL-1beta-induced regulatory pathways and selectively to suppress inflammatory 
      responses in synovial fibroblasts. The results of this study provide a rationale 
      for examining the use of IDR-peptides as potential therapeutic candidates for 
      chronic inflammatory diseases such as inflammatory arthritis.
FAU - Turner-Brannen, Emily
AU  - Turner-Brannen E
AD  - Manitoba Centre for Proteomics and Systems Biology, Department of Internal 
      Medicine, University of Manitoba, 799 John Buhler Research Centre, 715 McDermot 
      Avenue, Winnipeg, MB, R3E3P4, Canada.
FAU - Choi, Ka-Yee
AU  - Choi KY
FAU - Lippert, Dustin N D
AU  - Lippert DN
FAU - Cortens, John P
AU  - Cortens JP
FAU - Hancock, Robert E W
AU  - Hancock RE
FAU - El-Gabalawy, Hani
AU  - El-Gabalawy H
FAU - Mookherjee, Neeloffer
AU  - Mookherjee N
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110811
PL  - England
TA  - Arthritis Res Ther
JT  - Arthritis research & therapy
JID - 101154438
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Antimicrobial Cationic Peptides)
RN  - 0 (Cytokines)
RN  - 0 (IDR 1002)
RN  - 0 (Interleukin-1beta)
SB  - IM
MH  - Anti-Inflammatory Agents/*pharmacology
MH  - Antimicrobial Cationic Peptides/*pharmacology
MH  - Blotting, Western
MH  - Cell Separation
MH  - Cells, Cultured
MH  - Cytokines/biosynthesis
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Fibroblasts/*drug effects/immunology
MH  - Flow Cytometry
MH  - Humans
MH  - Immunohistochemistry
MH  - Inflammation/chemically induced/*immunology
MH  - Interleukin-1beta/immunology/metabolism/pharmacology
MH  - Real-Time Polymerase Chain Reaction
MH  - Signal Transduction/*drug effects/immunology
MH  - Synovial Membrane/drug effects/immunology
PMC - PMC3239371
EDAT- 2011/08/13 06:00
MHDA- 2012/03/30 06:00
PMCR- 2011/08/11
CRDT- 2011/08/13 06:00
PHST- 2011/02/08 00:00 [received]
PHST- 2011/04/01 00:00 [revised]
PHST- 2011/08/11 00:00 [accepted]
PHST- 2011/08/13 06:00 [entrez]
PHST- 2011/08/13 06:00 [pubmed]
PHST- 2012/03/30 06:00 [medline]
PHST- 2011/08/11 00:00 [pmc-release]
AID - ar3440 [pii]
AID - 10.1186/ar3440 [doi]
PST - epublish
SO  - Arthritis Res Ther. 2011 Aug 11;13(4):R129. doi: 10.1186/ar3440.