One of the major characteristics of
tumors is their ability to evade immunosurveillance through altering the properties and functions of host stromal and/or immune cells. CCL5 has been shown to play important roles in T cell proliferation, IFN-γ, and
IL-2 production, which promotes the differentiation and proliferation of Th1 cells important for immune defense against intracellular
infection. In this study we found that
tumor-bearing mice were more susceptible to
bacterial infection and showed reduced CCL5 levels in serum during endotoxic
shock. Our data further demonstrated that the soluble factors secreted by mammary gland
tumor cells but not normal mammary gland epithelial cells inhibited CCL5 expression in macrophages in response to LPS, but not to TNF-α stimulation. The inhibitory effect of
tumor-secreted molecules on LPS-induced CCL5 expression was regulated at the post-transcriptional level. Blocking
PGE(2) synthesis by
NS398 or through the use of
PGE(2) receptor antagonists
AH-6809 (EP2 antagonist) and
AH-23848 (EP4 antagonist) completely reversed the inhibitory effect of
tumor-
conditioned medium (TCM) on LPS-induced CCL5 expression. Moreover,
PGE(2) and the cAMP analog
forskolin could mimic
tumor-mediated CCL5 inhibition, and the inhibitory effects of TCM,
PGE(2), and cAMP analog on LPS-induced CCL5 expression could be completely reversed by the
PKA inhibitor H89. Furthermore, blocking
PGE(2) synthesis in vivo led to partial recovery of CCL5 production during endotoxic
shock. Taken together, our data indicate that
PGE(2) secreted from
breast cancer cells suppresses CCL5 secretion in LPS-activated macrophages through a cAMP/PKA signaling pathway, which may result in suppression of host immune responses against subsequent
bacterial infection.