Abstract
Although granulocytes are the most abundant leukocytes in human blood, their involvement in the immune response against cancer is not well understood. While granulocytes are known for their “oxidative burst” when challenged with tumor cells, it is less known that oxygen-dependent killing of tumor cells by granulocytes includes peroxidation of lipids in tumor cell membranes, yielding formation of reactive aldehydes like 4-hydroxynonenal (4-HNE) and acrolein. In the present work, we investigate the role of reactive aldehydes on cellular redox homeostasis and surface toll-like receptor 4 (TLR4) expression. We have further study the granulocyte-tumor cell intercellular redox signaling pathways. The data obtained show that granulocytes in the presence of 4-HNE and acrolein induce excessive ROS formation in tumor cells. Acrolein was also shown to induce granulocyte TLR4 expression. Furthermore, granulocyte-mediated antitumor effects were shown to be mediated via HOCl intracellular pathway by the action of NADPH oxidase. However, further studies are needed to understand interaction between TLR4 and granulocyte-tumor cell intercellular signaling pathways.
Highlights
Granulocytes are the most abundant leukocytes in the human body, which provide the first line of defense against pathogens and play a fundamental role in the innate immune response [1]
Granulocytes themselves did not influence intracellular reactive oxygen species (ROS) production in W256 cancer cells (Figure 1B, p > 0.05), while the addition of both reactive aldehydes caused a significant increase of intracellular ROS production by cancer cells (Figure 1B, p < 0.05, for both 4-HNE and acrolein)
The role of granulocytes in the host’s defense against cancer is not well understood, the important role of granulocyte-derived ROS in the oxygen-dependent killing of tumor cells was recognized more than 30 years ago [28]
Summary
Granulocytes are the most abundant leukocytes in the human body, which provide the first line of defense against pathogens and play a fundamental role in the innate immune response [1]. Activated granulocytes generate vast amounts of reactive oxygen species (ROS) that were shown to be crucial for the oxygen-dependent killing of tumor cells [5,6]. ROS generation by activated granulocytes involves various mechanisms, among which NADPH oxidase seems to be the key source of granulocyte derived ROS during the oxidative burst [7,8]. Activation of NADPH oxidase was shown to be toll-like receptor 4 (TLR4)-dependent in response to hemorrhagic shock or pathogens [9,10]. Over a decade ago it was suggested that a tumor cell-induced oxidative burst of granulocytes could be via activation of toll-like receptors (TLR) [5], this still remains to be elucidated
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