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Cytokine‐activated human vascular smooth muscle delays apoptosis of neutrophils: Relevance of interactions between cyclo‐oxygenase‐2 and colony stimulating factors

Leukocytes undergo programmed cell death (apoptosis) as part of the normal course of inflammatory responses. The colony stimulating factors (CSF) are important inhibitors of neutrophil apoptosis. We have recently shown that cytokines stimulate human vascular smooth muscle cells (HVSMCs) to release granulocyte macrophage‐CSF (GM‐CSF) and granulocyte‐CSF (G‐CSF)‐like immunoreactivity, and that the inflammatory form of cyclo‐oxygenase (COX‐2) differentially modulates their release. However, the biological relevance of these observations is not known. Here we have measured human neutrophil apoptosis as a bioassay for the activity of authentic GM‐CSF and G‐CSF, as well as products released by cytokine‐stimulated HVSMCs. Furthermore, we have assessed the biological relevance of COX‐2 in the production of survival‐promoting factors by HVSMCs. We demonstrate that (i) GM‐CSF is more potent than G‐CSF as an inhibitor of neutrophil apoptosis; (ii) of the two CSFs, the activity of G‐CSF released by HVSMCs predominates when cells are stimulated with cytokines; and (iii), this situation is reversed when COX activity is blocked such that GM‐CSF becomes the predominant active CSF produced by cells. These observations identify HVSMCs as important modulators of inflammatory and immune responses and identify a setting where COX‐2 activity regulates neutrophil survival indirectly via the production of CSFs.