Artherosclerosis
2007/4/23/7
Microbes
Infect. 2007 Feb 24; [Epub ahead of
print] TRAF activation of C/EBPbeta (NF-IL6) via p38 MAPK induces HIV-1 gene expression
in monocytes/macrophages. ·
Horie
R, Ishida T, Maruyama-Nagai M,
Ito K, Watanabe M,
Yoneyama
A, Higashihara
M, Kimura S, Watanabe T.
Department of Hematology, C/EBPbeta plays a pivotal
role in activation of human immunodeficiency virus type 1 (HIV-1) in monocytes/macrophages. However, mechanisms for
functional regulation of C/EBPbeta remain
uncharacterized. Previous studies indicated that NF-kappaB
activation by tumor necrosis factor (TNF) receptor family, which activates
TNF receptor associated factor (TRAF), induces HIV-1 expression. We found
that TRAF signals activate HIV-1 LTR with mutations of NF-kappaB sites in promonocytic
cell line U937, suggesting existence of an alternative HIV-1 activating
pathway. In this study, we have characterized the signal transduction
pathway of TRAF other than that leading to NF-kappaB,
using U937 cell line, and its subline, U1, which
is chronically infected by HIV-1. We show that signals downstream of TRAF2
and TRAF5 activate p38 MAPK, which directly phosphorylates
C/EBPbeta, and that activation of p38 MAPK
potently activates C/EBPbeta-mediated induction
of HIV-1 gene expression. We also show TRAF2 and TRAF5 are expressed in monocytes/macrophages of spleen samples from HIV-1
infected patients. Identification of TRAF-p38 MAPK-CEBPbeta
pathway provides a new target for controlling reactivation of latent HIV-1
in monocytes/macrophages. PMID: 17409010 [PubMed - as
supplied by publisher Proc
Natl Acad Sci U S A. 2007 Apr 10;104(15):6371-6.
Epub 2007 Apr 2. Ubiquitin-conjugating enzyme Ubc13 is a critical component
of TNF receptor-associated factor (TRAF)-mediated inflammatory responses. ·
Fukushima T,
Matsuzawa S,
Kress CL, Bruey
JM, Krajewska
M, Lefebvre S,
Zapata JM,
Ronai
Z, Reed JC. Burnham Institute for Medical
Research, 10901 North Torrey Ubc13 is a ubiquitin-conjugating enzyme responsible for noncanonical ubiquitination
of TNF receptor-associated factor (TRAF)-family adapter proteins involved
in Toll-like receptor and TNF-family cytokine receptor signaling, which are
regulators of innate immunity. Gene ablation was used to study the function
of Ubc13 in mice. Whereas homozygous ubc13 gene disruption resulted in
embryonic lethality, heterozygous ubc13(+/-) mice
appeared normal, without alterations in immune cell populations. Haploinsufficient ubc13(+/-)
mice were resistant to lipopolysaccharide-induced
lethality, and demonstrated reduced in vivo ubiquitination
of TRAF6. Macrophages and splenocytes isolated
from ubc13(+/-) mice exhibited reduced lipopolysaccharide-inducible cytokine secretion and
impaired activation of TRAF-dependent signal transduction pathways (NF-kappaB, JNK, and p38 MAPK). These findings document a
critical role for Ubc13 in inflammatory responses and suggest that agents
reducing Ubc13 activity could have therapeutic utility. PMID: 17404240 [PubMed - in
process] Arterioscler Thromb Vasc Biol. 2007 May;27(5):1101-7.
Epub 2007 Mar 1. TRAF-1, -2, -3, -5, and
-6 are induced in atherosclerotic plaques and differentially mediate proinflammatory functions of CD40L in endothelial
cells. ·
Zirlik
A, Bavendiek
U, Libby P, MacFarlane L,
Gerdes
N, Jagielska
J, Ernst S, Aikawa
M, Nakano H, Tsitsikov
E, Schonbeck
U. Donald W. Reynolds Cardiovascular Research
Center, Department of Medicine, Brigham and Women's Hospital and Harvard
Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. OBJECTIVE: Several lines of evidence implicate CD40 ligand (CD40L, CD154) as a mediator and marker of
atherosclerosis. This study investigated the involvement of tumor necrosis
factor receptor-associated factors (TRAFs) in CD40
signaling in endothelial cells (ECs) and their
expression in atheromata and cells involved in atherogenesis. METHODS AND RESULTS: CD40L enhanced the
basal expression of TRAF-1, -2, -3, and 6, but not TRAF-5 in ECs. TRAFs associated with
CD40 on ligation by CD40L. Study of ECs from TRAF-1, -2, and -5-deficient mice demonstrated
functional involvement of TRAFs in proinflammatory CD40 signaling. Whereas TRAF-1
deficiency enhanced CD40L-induced IL-6 and MCP-1 expression, TRAF-2 and
TRAF-5 deficiency inhibited CD40L-inducible IL-6 but not MCP-1 expression.
Gene silencing in human ECs further delineated
functions of TRAFs in CD40 signaling. TRAF-3
silencing in ECs showed increased CD40L-induced
IL-6, MCP-1, and IL-8 expression, whereas TRAF-6 silencing increased
selectively CD40L-induced MCP-1 expression. Enhanced TRAF
levels in atherosclerotic lesions further supports involvement of members
of this family of signaling molecules in arterial disease.
CONCLUSIONS: These results implicate endothelial TRAF-1, -2, -3, -5, and -6
in CD40 signaling in atherogenesis, identifying
these molecules as potential targets for selective therapeutic
intervention. PMID: 17332487 [PubMed - in process
