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Cytosolic Phospholipase A₂ Participates with TNF- in the Induction of Apoptosis of Human Macrophages Infected with Mycobacterium tuberculosis H37Ra¹

Lei Duan^*, Huixian Gan^*, Jonathan Arm^*, and Heinz G. Remold^2,*

^* Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital and Harvard Medical School, Boston MA 02115; and Partners Asthma Center, Brigham and Women’s Hospital, Boston, MA 02115

Macrophage (M) apoptosis, an important innate microbial defense mechanism induced by Mycobacterium tuberculosis (Mtb) H37Ra, depends on the induction of TNF- synthesis. When protein synthesis is blocked, both infection with Mtb and addition of TNF- are required to induce caspase 9 activation, caspase 3 activation and apoptosis. In this study, we show that the second protein synthesis-independent signal involves activation of group IV cytosolic phospholipase A₂ (cPLA₂). Apoptosis of Mtb-infected M and concomitant arachidonic acid release are abrogated by group IV cPLA₂ inhibitors (methyl arachidonyl fluorophosphate and methyl trifluoromethyl ketone), but not by inhibitors of group VI Ca²⁺-independent (iPLA₂ ; bromoenol lactone) or of secretory low molecular mass PLA₂. In M homogenates, the predominant PLA₂ activity showed the same inhibitor sensitivity pattern and preferred arachidonic acid over palmitic acid in substrates, also indicating the presence of one or more group IV cPLA₂ enzymes. In concordance with these findings, M lysates contained transcripts and protein for group IV cPLA₂- and cPLA₂-. Importantly, group IV cPLA₂ inhibitors significantly reduced M antimycobacterial activity and addition of arachidonic acid, the major product of group IV cPLA₂, to infected M treated with cPLA₂ inhibitors completely restored the antimycobacterial activity. Importantly, addition of arachidonic acid alone to infected M significantly reduced the mycobacterial burden. These findings indicate that Mtb induces M apoptosis by independent signaling through at least two pathways, TNF- and cPLA₂, which are both also critical for antimycobacterial defense of the M .

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