EDITORIAL
Re: “Collagen-Induced Arthritis in TNF Receptor-1-Deficient Mice: TNF
Receptor-2 Can Modulate Arthritis in the Absence of TNF Receptor 1”
John D. Mountz
Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama,
701 South 19th Street, LHRB 473, Birmingham, Alabama 35294
The relative contributions of TNFR1 and TNFR2
signaling in TNF-induced proinflammatory response
leading to arthritis as well as an anti-inflammatory or
proapoptotic death have been difficult to establish. In T
cells, signaling through both TNFR1 and TNFR2 can
activate caspase 8, leading to a proapoptotic signal as
well as to activation of NF-
B, which leads to a proin-
flammatory, antiapoptotic signal. Signaling through
TNFR1 couples to the apoptosis pathway through the
adapter molecules TNF receptor-associated death do-
main (TRADD) and Fas-associated death domain
(FADD) to dock with caspase 8 (1–3) (Fig. 1). Similarly,
signaling through TNFR2 signals through TRAF2,
which leads to recruitment of RIP3 (4). The death
domain of RIP3 binds to FADD, which activates
caspase 8, leading to apoptosis signaling (5). TNFR1
apoptosis signaling occurs in many cell types, whereas
TNFR2 apoptosis signaling is more restricted to T
cells.
The antiapoptotic or proinflammatory signal is me-
diated by both TNFR1 and TNFR2, which are primar-
ily signaled by TNF receptor-associated factor 2
(TRAF2) and then in the case of TNFR1, RIP1 and 2,
leading to activation of NF-
B (6). NF-
B leads to
antiapoptosis signaling by upregulation of several an-
tiapoptosis genes (7, 8) and also can directly signal a
proinflammatory signal leading to release of TNF-
␣
and IL-1

.
The role of TNFR2 signaling in T cells is of interest
especially in arthritis because it has been shown that,
on resting or suboptimally signaled naı¨ve T cells, TNF
stimulates proliferation through the TNFR2 pathway
(9–11). However, after activation, signaling through
TNFR2 leads to apoptosis through a pathway involving
TRAF2 and RIP3 interaction with FADD and caspase 8
(5). Thus the use of a proinflammatory or proapoptosis
or anti-inflammatory signal through TNFR2 in T cells
is dependent upon the prior activation state of T cells
(12–14).
In this issue, Tada et al. (15) describe their investi-
gation of CII arthritis in TNFR1 knockout mice. These
results indicate that the incidence of severity of induc-
tion of CII arthritis in TNFR1 knockout mice is similar
to that in mice that express TNFR1 and TNFR2. This
is consistent with previous observations that signaling
through TNFR1 may have both anti-inflammatory and
proinflammatory responses, consistent with the dual
signaling nature of TNFR1. The results of Tada et al.
also demonstrate that signaling through TNFR2 is suf-
ficient for development of arthritis. This may be en-
hanced by the higher levels of TNF-
␣
observed in the
arthritic joints of the TNFR1-deficient mice. The re-
sults are also consistent with utilization of an apopto-
sis signaling or anti-inflammatory signaling pathway
through TNFR1, as demonstrated by the observation
that neutralization of TNF with soluble TNF binding
protein (TNF
bp
) during the late phase of arthritis (days
29–39) suppresses arthritis in mice expressing both
TNFR1 and TNFR2, but not in mice expressing TNFR2
alone. These results suggest that, in CII arthritis-sus-
ceptible strains of mice, TNFR1 signaling exhibits pre-
dominantly a proarthritis propensity, consistent with
either a defect in the apoptosis pathway or an increase
in the antiapoptosis pathway. This result also suggests
that in the absence of TNFR1, TNFR2 signaling can
exert an antiarthritis signal, in the late phase of CIA
arthritis development. This is consistent with the con-
cept that TNFR2 can exhibit primarily an apoptosis
signaling in activated T cells (12, 13).
In this issue, Tada et al. also show that TNF-
␣
ad-
ministered early during the initiation phase of arthri-
tis (days 2–20) enhances development of arthritis but
inhibits arthritis if administered during the late, pro-
gressive stage. This is consistent with a selection for
proinflammatory T cells or synovial fibroblasts that are
apoptosis resistant in the early phase that enhances
arthritis. The role of TNF-
␣
signaling through TNFR1
was investigated by administration of human TNF-
␣
,
which binds only to TNFR1. In contrast to results
Clinical Immunology
Vol. 99, No. 3, June, pp. 305–307, 2001
doi:10.1006/clim.2001.5030, available online at http://www.idealibrary.com on
1521-6616/01 $35.00
Copyright © 2001 by Academic Press
All rights of reproduction in any form reserved.
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