J. Reinartz et al., TUMOR NECROSIS FACTOR-ALPHA-INDUCED APOPTOSIS IN A HUMAN KERATINOCYTECELL-LINE (HACAT) IS COUNTERACTED BY TRANSFORMING GROWTH-FACTOR-ALPHA, Experimental cell research, 228(2), 1996, pp. 334-340
The integrity of the human epidermis is guaranteed by a regulated bala
nce of proliferation, differentiation, and physiologic cell death of i
ts main cellular constituent, the epidermal keratinocyte. Physiologic
cell death is known as apoptosis and has been recognized as an active
regulatory mechanism, complementary to, but functionally opposite of,
proliferation. The regulators of the delicate balance between cell dea
th and proliferation are only partially understood in human keratinocy
tes. Transforming growth factor-alpha (TGF-alpha) has been identified
as a positive regulator of proliferation and growth, while tumor necro
sis factor-alpha (TNF-alpha) induces apoptosis. Both mediators are tho
ught to influence epidermal keratinocytes under various physiological
and pathophysiological conditions. In the current study we have begun
to investigate potential regulatory interactions between these two med
iators in the human keratinocyte cell line HaCaT. We have found that,
when the HaCaT cells were sensitized by the translation inhibitor cycl
oheximide, TNF-alpha induced apoptosis, as evidenced by nuclear disint
egration, DNA fragmentation (''DNA laddering''), and the appearance of
soluble DNA/histone complexes. Moreover, we found that the induction
of apoptosis was reduced by preincubation of the cells with TGF-alpha.
The protective effect of TGF-alpha was abrogated by translation inhib
ition, indicating that it depended on de novo protein synthesis. Moreo
ver, the protective effect was not accompanied by a reduced surface ex
pression of TNF receptor molecules. We postulate that TNF-alpha-induce
d apoptosis in HaCaT cells is counteracted by constitutively produced
suppressors of apoptosis, the synthesis of which can be downregulated
by inhibition of translation and upregulated by the cytokine TGF-alpha
. (C) 1996 Academic Press, Inc.