EXPRESSION OF THE TYPE-II PHOSPHOLIPASE A(2) IN ALVEOLAR MACROPHAGES - DOWN-REGULATION BY AN INFLAMMATORY SIGNAL

We have shown previously that guinea pig alveolar macrophages (AM) syn thesize a secretory phospholipase A(2) (PLA(2)) during in vitro incuba tion. Here, we report the molecular cloning of this enzyme and show th at it has structural features closely related to all known mammalian t ype-II PLA(2). The mRNA and PLA(2) activity were undetectable in fresh ly collected AM, but their levels increased dramatically to reach maxi mal values after 16 h of culture. Thereafter, the PLA(2) activity rema ined constant with a parallel secretion in the medium, in contrast to mRNA level which returned to near basal values after 32 h. Incubation of AM for 16 h with the inflammatory secretagogue peptide f-Met-Leu-Ph e (fMLP) markedly reduced the PLA(2) activity and mRNA levels. This in hibition was prevented by preexposure of AM to pertussis toxin, an inh ibitor of G-protein. In contrast, when AM were first cultured for 16 h and then incubated with fMLP, no significant change was observed in t heir PLA(2) activity. In conditions where the type-II PLA(2) was compl etely abrogated by fMLP, the latter did not alter the lipopolysacchari de-induced accumulation of tumor necrosis factor ru mRNA or the releas e of arachidonic acid induced by the subsequent addition of the calciu m ionophore A23187. These studies show that the inflammatory peptide f MLP down-regulates the expression of the type-II PLA(2) by AM through a process mediated by G-protein. A possible negative control of the ty pe-II PLA(2) expression during AM activation is suggested.