We have read with great interest the article by Halili et al. [1], in which the authors propose that TSA suppresses the LPSinduced mRNA expression of the proinflammatory mediators endothelin-1, Ccl-7/MCP-3, and IL-12p40 but amplifies the expression of the proatherogenic factors Cox-2 and Pai-1 in mouse BMM.We totally agree with the initial reflections made by the authors relating the complexity of the effects exerted by HDAC inhibitors, not only in macrophages but also in other cell types, and the existence of even contradictory effects, some of them anti-inflammatory or antiproliferative, although others are clearly proinflammatory. However, we find very difficult to appreciate or support how the authors reached those reflections regarding the value or involvement of apoptosis on the observed effects of TSA.The differences observed in the effects of HDAC inhibitors based on a gradient of drug concentration in macrophages could be easily related to the fact that these HDAC inhibitors are not selective. Moreover, we and others [2,3] have seen previously that the sensitivity of HDAC inhibitors also depends on several factors, including the differentiation state, confluence, or proliferative rate of different cell types. Similarly to the authors, we have also addressed the relation between macrophage proliferation/viability/activation and HDAC effects [3]. In this regard, our previous data suggest that in those cells in which the activation stimuli do not affect proliferation, such as intestinal epithelial cells, or even induce proliferation, such as lymphocytes, butyrate (a pan-HDAC inhibitor) inhibits activation almost totally through the induction of apoptosis; in contrast, in those cells, such as bone marrow macrophages, whose activation induces a blockage of the proliferation, butyrate is unable to inhibit their activation and slightly affects cellular survival. Inasmuch, even in the same cellular type, such as the case of macrophages, LPS-activated RAW 264.7 (as a proliferating cell line) and LPS-activated BMM (quiescent primary cultures) present different proinflammatory responses [3].However, these studies are always made at physiological butyrate concentrations, and it is therefore difficult for us to understand the rationale behind the nonpharmacological range of concentrations selected by the authors to test the effects of the HDAC inhibitors [1], as they are more than one log higher than the dose required to inhibit HDAC. Moreover, we do not understand the conclusions drawn by the authors that the high degree of cell death induced by these concentrations is not relevant or involved in the observed effects.Cell death at the degrees observed by the authors (Ͻ20% of viability after stimuli) should always be taken in consideration. Although the authors clearly observed that the Cox-2-and Pai-1-induced expression is observed only at these concentrations and with those inhibitors that clearly affect cell viability [1], they conclude that the induction of apoptosis is not responsible for this observed effect, ...