calpain-inhibitor-iii and Lung-Neoplasms

Macrophages highly populate tumour microenvironment and are referred to as tumor-associated macrophages (TAMs). The inflammasome is a multiprotein complex responsible of IL-1 like cytokines release, which biology has been widely studied by using bone-marrow-derived macrophages to mimic a physiological and/or host defense condition. To understand the role of this complex in lung tumor-associated macrophages (TAMs), we isolated and cultured broncho-alveolar lavage (BAL)-derived cells of lung tumor-bearing mice. The stimulation of lung TAMs with LPS+ATP increased the release of IL-1β. The inhibition of NLRP3 by means of glybenclamide significantly reduced IL-1β release. Similarly, C3H-derived, caspase-1 ko and caspase-11 ko TAMs released significantly reduced levels of IL-1β. Moreover, the stimulation of lung TAMs with the sole LPS induced a significant release of IL-1α, which was significantly reduced after caspase-1 pharmacological inhibition, and in TAMs genetically lacking caspase-1 and caspase-11. The inhibition of calpain I/II by means of MDL28170 did not alter IL-1α release after LPS treatment of lung TAMs. To note, the inoculation of LPS-treated bone marrow-derived macrophages into carcinogen-exposed mice increased lung tumor formation. In contrast, the depletion of TAMs by means of clodronate liposomes reduced lung tumorigenesis, associated to lower in vivo release of IL-1α and IL-1β.In conclusion, our data imply lung tumor lesions are populated by macrophages which pro-tumor activity is regulated by the activation of the NLRP3 inflammasome that leads to the release of IL-1α and IL-1β in a caspase-11/caspase-1-dependent manner.

Topics: Adenosine Triphosphate; Animals; Bronchoalveolar Lavage Fluid; Calpain; Carcinogenesis; Caspase 1; Caspase Inhibitors; Caspases; Caspases, Initiator; Cells, Cultured; Clodronic Acid; Dipeptides; Female; Glyburide; Inflammasomes; Interleukin-1alpha; Interleukin-1beta; Lipopolysaccharides; Lung Neoplasms; Macrophages, Alveolar; Methylnitrosourea; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Neoplasms, Experimental; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction; Specific Pathogen-Free Organisms; Toll-Like Receptor 4