PMID- 25051892
OWN - NLM
STAT- MEDLINE
DCOM- 20150210
LR  - 20211021
IS  - 1365-2567 (Electronic)
IS  - 0019-2805 (Print)
IS  - 0019-2805 (Linking)
VI  - 144
IP  - 1
DP  - 2015 Jan
TI  - Blockade of CD40-TRAF2,3 or CD40-TRAF6 is sufficient to inhibit pro-inflammatory 
      responses in non-haematopoietic cells.
PG  - 21-33
LID - 10.1111/imm.12361 [doi]
AB  - Inhibition of the CD40-CD154 pathway controls inflammatory disorders. 
      Unfortunately, administration of anti-CD154 monoclonal antibodies causes 
      thromboembolism. Blockade of signalling downstream of CD40 may represent an 
      approach to treat CD40-driven inflammatory disorders. Blocking tumour necrosis 
      factor receptor-associated factor 6 (TRAF6) signalling downstream of CD40 in MHC 
      II(+) cells diminishes inflammation. However, CD40-TRAF6 blockade may cause 
      immunosuppression. We examined the role of CD40-TRAF2,3 and CD40-TRAF6 signalling 
      in the development of pro-inflammatory responses in human non-haematopoietic and 
      monocytic cells. Human aortic endothelial cells, aortic smooth muscle cells, 
      renal proximal tubule epithelial cells, renal mesangial cells and monocytic cells 
      were transduced with retroviral vectors that encode wild-type CD40, CD40 with a 
      mutation that prevents TRAF2,3 recruitment (DeltaT2,3), TRAF6 recruitment (DeltaT6) or 
      both TRAF2,3 plus TRAF6 recruitment (DeltaT2,3,6). Non-haematopoietic cells that 
      expressed CD40 DeltaT2,3 exhibited marked inhibition in CD154-induced up-regulation 
      of vascular cell adhesion molecule 1, intercellular adhesion molecule 1 (ICAM-1), 
      monocyte chemotactic protein 1 (MCP-1), tissue factor and matrix 
      metalloproteinase 9. Similar results were obtained with cells that expressed CD40 
      DeltaT6. Although both mutations impaired ICAM-1 up-regulation in monocytic cells, 
      only expression of CD40 DeltaT6 reduced MCP-1 and tissue factor up-regulation in 
      these cells. Treatment of endothelial and smooth muscle cells with cell-permeable 
      peptides that block CD40-TRAF2,3 or CD40-TRAF6 signalling impaired 
      pro-inflammatory responses. In contrast, while the CD40-TRAF2,3 blocking peptide 
      did not reduce CD154-induced dendritic cell maturation, the CD40-TRAF6 blocking 
      peptide impaired this response. Hence, preventing CD40-TRAF2,3 or CD40-TRAF6 
      interaction inhibits pro-inflammatory responses in human non-haematopoietic 
      cells. In contrast to inhibition of CD40-TRAF6 signalling, inhibition of 
      CD40-TRAF2,3 signalling did not impair dendritic cell maturation. Blocking 
      CD40-TRAF2,3 signalling may control CD40-CD154-dependent inflammatory disorders.
CI  - (c) 2014 John Wiley & Sons Ltd.
FAU - Portillo, Jose-Andres C
AU  - Portillo JA
AD  - Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case 
      Western Reserve University, Cleveland, OH, USA.
FAU - Greene, Jennifer A
AU  - Greene JA
FAU - Schwartz, Isaac
AU  - Schwartz I
FAU - Subauste, Maria Cecilia
AU  - Subauste MC
FAU - Subauste, Carlos S
AU  - Subauste CS
LA  - eng
GR  - P30 CA043703/CA/NCI NIH HHS/United States
GR  - R01 EY019250/EY/NEI NIH HHS/United States
GR  - P30 CA43703/CA/NCI NIH HHS/United States
GR  - EY019250/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Immunology
JT  - Immunology
JID - 0374672
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (CCL2 protein, human)
RN  - 0 (CD40 Antigens)
RN  - 0 (Chemokine CCL2)
RN  - 0 (ICAM1 protein, human)
RN  - 0 (Peptides)
RN  - 0 (TNF Receptor-Associated Factor 2)
RN  - 0 (TNF Receptor-Associated Factor 3)
RN  - 0 (TNF Receptor-Associated Factor 6)
RN  - 0 (TRAF3 protein, human)
RN  - 126547-89-5 (Intercellular Adhesion Molecule-1)
RN  - 147205-72-9 (CD40 Ligand)
RN  - 9035-58-9 (Thromboplastin)
RN  - EC 1.11.1.- (Peroxidases)
RN  - EC 1.11.1.- (microperoxidase)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents, Non-Steroidal/*pharmacology
MH  - CD40 Antigens/*antagonists & inhibitors/genetics/immunology
MH  - CD40 Ligand/genetics/immunology
MH  - Cell Line
MH  - Chemokine CCL2/genetics/immunology
MH  - Dendritic Cells/immunology/pathology
MH  - Endothelial Cells/immunology/pathology
MH  - Humans
MH  - Inflammation/drug therapy/genetics/immunology
MH  - Intercellular Adhesion Molecule-1/genetics/immunology
MH  - Mesangial Cells/immunology/pathology
MH  - Mice
MH  - Myocytes, Smooth Muscle/immunology/pathology
MH  - Peptides/*pharmacology
MH  - Peroxidases/genetics/immunology
MH  - Signal Transduction/drug effects/genetics/immunology
MH  - TNF Receptor-Associated Factor 2/*antagonists & inhibitors/genetics/immunology
MH  - TNF Receptor-Associated Factor 3/*antagonists & inhibitors/genetics/immunology
MH  - TNF Receptor-Associated Factor 6/*antagonists & inhibitors/genetics/immunology
MH  - Thromboplastin/genetics/immunology
MH  - Up-Regulation/drug effects/genetics/immunology
PMC - PMC4264907
OTO - NOTNLM
OT  - endothelial cell
OT  - epithelial cell
OT  - inflammation
OT  - monocyte
OT  - muscle smooth cell
EDAT- 2014/07/24 06:00
MHDA- 2015/02/11 06:00
PMCR- 2016/01/01
CRDT- 2014/07/24 06:00
PHST- 2014/05/01 00:00 [received]
PHST- 2014/06/11 00:00 [revised]
PHST- 2014/06/11 00:00 [accepted]
PHST- 2014/07/24 06:00 [entrez]
PHST- 2014/07/24 06:00 [pubmed]
PHST- 2015/02/11 06:00 [medline]
PHST- 2016/01/01 00:00 [pmc-release]
AID - 10.1111/imm.12361 [doi]
PST - ppublish
SO  - Immunology. 2015 Jan;144(1):21-33. doi: 10.1111/imm.12361.