MURINE ALPHA-MACROGLOBULINS DEMONSTRATE DIVERGENT ACTIVITIES AS NEUTRALIZERS OF TRANSFORMING GROWTH-FACTOR-BETA AND AS INDUCERS OF NITRIC-OXIDE SYNTHESIS - A POSSIBLE MECHANISM FOR THE ENDOTOXIN INSENSITIVITY OF THE ALPHA(2)-MACROGLOBULIN GENE KNOCK-OUT MOUSE
Dj. Webb et al., MURINE ALPHA-MACROGLOBULINS DEMONSTRATE DIVERGENT ACTIVITIES AS NEUTRALIZERS OF TRANSFORMING GROWTH-FACTOR-BETA AND AS INDUCERS OF NITRIC-OXIDE SYNTHESIS - A POSSIBLE MECHANISM FOR THE ENDOTOXIN INSENSITIVITY OF THE ALPHA(2)-MACROGLOBULIN GENE KNOCK-OUT MOUSE, The Journal of biological chemistry, 271(40), 1996, pp. 24982-24988
alpha(2)-Macroglobulin null mice demonstrate increased resistance to e
ndotoxin challenge (Umans, L., Serneels, L., Overbergh, L., Van Leuven
, F., and Van den Berghe, H. (1995) J. Biol. Chem. 270, 19778-19785).
We hypothesized that this phenotype might reflect the function of muri
ne alpha(2)M (m alpha(2)M) as a neutralizer of transforming growth fac
tor-beta (TGF-beta) and inducer of nitric oxide synthesis in vivo. Whe
n incubated with wild-type mouse plasma, TGF-beta 1 and TGF-beta 2 bou
nd only to m alpha(2)M. Alternative TGF-beta-binding proteins were not
detected in plasma from alpha(2)M(-/-) mice. Wild-type mouse plasma,
but not plasma from alpha(2)M(-/-) mice, inhibited TGF-beta 1 binding
to TGF-beta receptors on fibroblasts. Purified alpha(2)M bound TGF-bet
a 1 and TGF-beta 2 with similar affinity; the K-D values were 28 +/- 4
and 33 +/- 4 nm, respectively. Murinoglobulin, the second murine cu-m
acroglobulin, bound both TGF-beta isoforms with 30-fold lower affinity
, M alpha(2)M counteracted the activities of TGF-beta 1 and TGF-beta 2
in an endothelial cell growth assay. M alpha(2)M also induced NO synt
hesis when incubated with RAW 264.7 cells, an activity which probably
results from the neutralization of autocrine TGF-beta activity. Human
alpha(2)M induced NO synthesis comparably to m alpha(2)M; however, MUG
had no effect. These studies demonstrate that the ability to neutrali
ze TGF-beta is a property of m alpha(2)M, which is not redundant in th
e murine alpha-macroglobulin family or in murine plasma, M alpha(2)M i
s the only murine alpha-macroglobulin that promotes NO synthesis. The
absence of m alpha(2)M, in alpha(2)M(-/-) mice, may allow TGF-beta to
more efficiently suppress excessive iNOS expression following endotoxi
n challenge.