P. Peraldi et al., TUMOR-NECROSIS-FACTOR (TNF)-ALPHA INHIBITS INSULIN SIGNALING THROUGH STIMULATION OF THE P55 TNF RECEPTOR AND ACTIVATION OF SPHINGOMYELINASE, The Journal of biological chemistry, 271(22), 1996, pp. 13018-13022
Tumor necrosis factor (TNF)alpha plays a central role in the state of
insulin resistance associated with obesity. It has previously been sho
wn that one important mechanism by which TNF-alpha interferes with ins
ulin signaling is through the serine phosphorylation of insulin recept
or substrate-1 (IRS-1), which can then function as an inhibitor of the
tyrosine kinase activity of the insulin receptor (IR), However, the r
eceptors and the signaling pathway used by TNF-alpha that mediate the
inhibition of IR activity are unknown. We show here that human TNF-alp
ha, which binds only to the murine p55 TNF receptor (TNFR), is as effe
ctive at inhibiting insulin-dependent tyrosine phosphorylation of IR a
nd IRS-1 in adipocytes and myeloid 32D cells as murine TNF-alpha, whic
h binds to both p55 TNFR and p75 TNFR. Likewise, antibodies that are s
pecific agonists for p55 TNFR or p75 TNFR demonstrate that stimulation
of p55 TNFR is sufficient to inhibit insulin signaling, though a smal
l effect can also be seen with antibodies to p75 TNFR. Exogenous sphin
gomyelinase and ceramides, known to be formed by activat- ion of p55 T
NFR, inhibit IR and IRS-1 tyrosine phosphorylation and convert IRS-1 i
nto an inhibitor of IR tyrosine kinase in vitro. Myeloid 32D cells exp
ressing LR and IRS-1 are sensitive to this inhibition, but cells expre
ssing IR and IRS-2 are resistant, pointing to an important difference
in the biological function between IRS-1 and IRS-2. These data strongl
y suggest that TNF-alpha inhibits insulin signaling via stimulation of
p55 TNFR and sphingomyelinase activity, which results in the producti
on of an inhibitory form of IRS-1.