Diallyl disulfide inhibits TNFα induced CCL2 release through MAPK/ERK and NF-Kappa-B signaling

TNF alpha receptors are constitutively overexpressed in tumor cells, correlating to sustain elevated NF kappa B and monocyte chemotactic protein-1 (MCP-1/CCL2) expression. The elevation of CCL2 evokes aggressive forms of malignant tumors marked by tumor associated macrophage (TAM) recruitment, cell proliferation, invasion and angiogenesis. Previously, we have shown that the organo-sulfur compound diallyl disulfide (DADS) found in garlic (Allium sativum) attenuates TNF alpha, induced CCL2 production in MDA-MB-231 cells. In the current study, we explored the signaling pathways responsible for DADS suppressive effect on TNF alpha mediated CCL2 release using PCR Arrays, RT-PCR and western blots. The data in this study show that TNF alpha initiates a rise in NM mRNA, which is not reversed by DADS. However, TNF alpha, induced heightened expression of IKK epsilon and phosphorylated ERIC. The expression of these proteins corresponds to increased CCL2 release that can be attenuated by DADS. CCL2 induction by TNF alpha was also lessened by inhibitors of p38 (SB202190) and MEK (U0126) but not JNK (SP 600125), all of which were suppressed by DADS. In conclusion, the obtained results indicate that DADS down regulates TNF alpha invoked CCL2 production primarily through reduction of IKKe and phosphorylated-ERK, thereby impairing MAPK/ERK, and NF kappa B pathway signaling. Future research will be required to evaluate the effects of DADS on the function and expression of TNF alpha surface receptors. (C) 2015 Elsevier Ltd. All rights reserved.