L. Steiner et al., ENDOTHELIAL-CELLS AS CYTOTOXIC EFFECTOR-CELLS - CYTOKINE-ACTIVATED RAT ISLET ENDOTHELIAL-CELLS LYSE SYNGENEIC ISLET CELLS VIA NITRIC-OXIDE, Diabetologia, 40(2), 1997, pp. 150-155
In vivo, each beta cell is located in proximity to at least one capill
ary islet endothelial cell. Rat aorta and islet endothelial cells can
be activated in vitro to express inducible nitric oxide synthase by a
cytokine mixture of tumour necrosis factor-alpha, gamma-interferon, an
d interleukin-1 beta and to produce high concentrations of nitric oxid
e. We have performed co-culture experiments with rat islet endothelial
cells together with isolated syngeneic islet cells at low target:effe
ctor ratios with or without previous cytokine challenge of endothelial
cultures. Co-cultures were always free of exogenous cytokines, which
were removed prior to addition of islet cells. We found that pre-activ
ated, in contrast to resident islet endothelial cells, at a target:eff
ector ratio as low as 1:1 almost completely lysed syngeneic beta and n
on-beta cells within 24 h of co-culture. Lysis by pre-activated islet
endothelial cells was found to be preceded by DNA damage found in 46%
of islet cells after 8 h of co-culture with pre-activated vs 7% with r
esting islet endothelial cells. Lysis was blocked to control levels in
the presence of the nitric oxide synthase inhibitor N-G-methyl-L-argi
nine. With the results presented here, we demonstrate for the first ti
me, that activated endothelial lining cells can express effector cell
activity and thus can contribute to local tissue destruction, especial
ly in organs that are densely capillarized such as pancreatic islets.