Leukemia inhibitory factor via the Toll-like receptor 5 signaling pathway involves aggravation of cachexia induced by human gastric cancer-derived 85As2 cells in rats

Abstract

Cancer cachexia is highly prevalent in gastric cancer patients and characterizedby decreased food consumption and body weight. We previously created a rat modelof cancer cachexia using MKN45cl85 and 85As2 cells derived from human gastriccancer. The 85As2 cells induced cachexia more potently compared to MKN45cl85 cells.To clarify the mechanism underlying the difference in the cachexia-inducing abilityof these cells, we conducted DNA microarray analysis, focusing on cell proliferationand the production of leukemia inhibitory factor (LIF), a cachexia-inducing factor.The plasma human LIF levels of 85As2-induced cachexic rats increased as symptomsworsened, whereas the plasma levels of MKNcl85 were low. 85As2 cells displayedmore genetic changes compared to MKN45cl85 cells, which were related to Toll-likereceptor (TLR) 4/5 signaling. Stimulation of both cells with TLR4 (lipopolysaccharide)or TLR5 (flagellin) agonists did not affect proliferation. However, in 82As2 cells,LIF production was significantly increased by stimulation with TLR5, which wassuppressed by an inhibitor of interleukin-1 receptor-associated kinase-1/4, whichare important factors in the TLR5 signaling pathway. The increase in LIF productionresulting from activation of the TLR5 signaling pathway may contribute to thecachexia-inducing ability of 85As2 cells.