Hy. Zhang et al., REGULATION OF LUNG FIBROBLAST ALPHA-SMOOTH MUSCLE ACTIN EXPRESSION, CONTRACTILE PHENOTYPE, AND APOPTOSIS BY IL-1-BETA, The Journal of immunology, 158(3), 1997, pp. 1392-1399
IL-1 is important in regulating lung inflammation and potentially fibr
osis as well. To clarify the role of this cytokine vis-a-vis changes i
n lung fibroblast phenotype in pulmonary fibrosis, the effects of IL-1
beta on isolated lung fibroblasts were examined. Rat lung fibroblasts
were treated with increasing doses of IL-1 beta and examined for effe
cts on cell number, cu-smooth muscle actin expression, apoptosis, nitr
ic oxide (NO) production, and contractility in collagen gels, The resu
lts show that IL-1 beta caused dose-dependent down-regulation of alpha
-smooth muscle actin protein and mRNA expression. The kinetics of mRNA
inhibition was rapid and preceded the effects on protein expression.
This IL-1 beta-induced decrease in actin expression was associated wit
h inhibition of contractility evaluated using fibroblast-populated col
lagen gels. Since IL-1 beta inhibition of actin expression was accompa
nied by reduction in cell number, the effect on apoptosis was examined
. Significant increase in the number of apoptotic nuclei and DNA fragm
entation was observed upon IL-1 beta treatment, with a dose-response c
urve that mirrored that for the decline in actin-positive cells. More
than one-half of the apoptotic cells were actin positive at high IL-1
beta doses, suggesting that the actin-expressing cells may be more sus
ceptible to IL-1 beta-induced apoptosis. IL-1 beta also induced NO pro
duction in these cells, which was inhibited by NG-monomethyl-L-arginin
e. Similarly, IL-1 beta-induced apoptosis and inhibition of actin expr
ession were inhibited by this arginine analogue. Hence, induction of a
poptosis by IL-1 beta via NO production may be an important mechanism
for regulating lung fibroblast cu-smooth muscle actin expression, and
consequently its contractile phenotype as well.