Mr. Horton et al., Induction and regulation of macrophage metalloelastase by hyaluronan fragments in mouse macrophages, J IMMUNOL, 162(7), 1999, pp. 4171-4176
Although the metalloproteinase murine metalloelastase (MME) has been implic
ated in lung disorders such as emphysema and pulmonary fibrosis, the mechan
isms regulating MME expression are unclear. Low m.w. fragments of the extra
cellular matrix component hyaluronan (HA) that accumulate at sites of lung
inflammation are capable of inducing inflammatory gene expression in macrop
hages (M phi). The purpose of this study was to examine the effect of HA fr
agments on the expression of MIME in alveolar M phi. The mouse alveolar M p
hi cell line MH-S was stimulated with HA fragments over time, total RNA was
isolated, and Northern blot analysis was performed. HA fragments induced M
ME mRNA in a time-dependent fashion, with maximal levels at 6 h, HA fragmen
ts also induced MME protein expression as well as enzyme activity. The indu
ction of MME gene expression was specific for low m.w. HA fragments and dep
endent upon new protein synthesis; it occurred at the level of gene transcr
iption. We also examined the effect of HA fragments on MME expression in in
flammatory alveolar M phi from bleomycin-injured rat lungs, Although normal
rat alveolar M phi did not express MME mRNA in response to HA fragments, a
lveolar M phi from the bleomycin-treated rats responded to HA fragment stim
ulation by increasing MME mRNA levels. Furthermore, baseline and HA fragmen
t-induced MIME gene expression in alveolar M phi from bleomycin-treated rat
s was inhibited by IPN-gamma. These data suggest that HA fragments may be a
n important mechanism for the expression of MME by M phi in inflammatory lu
ng disorders.