title: CCL2 and interleukin-6 promote survival of human CD11b+ peripheral blood mononuclear cells and induce M2-type macrophage polarization.
abstract: CCL2 and interleukin (IL)-6 are among the most prevalent cytokines in the tumor microenvironment, with expression generally correlating with tumor progression and metastasis. CCL2 and IL-6 induced expression of each other in CD11b(+) cells isolated from human peripheral blood. It was demonstrated that both cytokines induce up-regulation of the antiapoptotic proteins cFLIP(L) (cellular caspase-8 (FLICE)-like inhibitory protein), Bcl-2, and Bcl-X(L) and inhibit the cleavage of caspase-8 and subsequent activation of the caspase-cascade, thus protecting cells from apoptosis under serum deprivation stress. Furthermore, both cytokines induced hyperactivation of autophagy in these cells. Upon CCL2 or IL-6 stimulation, CD11b(+) cells demonstrated a significant increase in the mannose receptor (CD206) and the CD14(+)/CD206(+) double-positive cells, suggesting a polarization of macrophages toward the CD206(+) M2-type phenotype. Caspase-8 inhibitors mimicked the cytokine-induced up-regulation of autophagy and M2 polarization. Furthermore, E64D and leupeptin, which are able to function as inhibitors of autophagic degradation, reversed the effect of caspase-8 inhibitors in the M2-macrophage polarization, indicating a role of autophagy in this mechanism. Additionally, in patients with advanced castrate-resistant prostate cancer, metastatic lesions exhibited an increased CD14(+)/CD206(+) double-positive cell population compared with normal tissues. Altogether, these findings suggest a role for CCL2 and IL-6 in the survival of myeloid monocytes recruited to the tumor microenvironment and their differentiation toward tumor-promoting M2-type macrophages via inhibition of caspase-8 cleavage and enhanced autophagy.
authors.affiliation: Department of Urology, University of Michigan, Ann Arbor, Michigan 48109, USA. rocach@umich.edu
authors.forename: Hernan
authors.initials: H
authors.lastname: Roca
authors.forename: Zachary S
authors.initials: ZS
authors.lastname: Varsos
authors.forename: Sudha
authors.initials: S
authors.lastname: Sud
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Craig
authors.forename: Chi
authors.initials: C
authors.lastname: Ying
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
mesh_terms: D001343:Autophagy; D039481:CD11b Antigen / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D018932:Chemokine CCL2 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000166:cytology*; D007976:Leupeptins / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D008264:Macrophages / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C494811:BCL2L1 protein, human; C111835:CCL2 protein, human; D039481:CD11b Antigen; D018932:Chemokine CCL2; D016207:Cytokines; C509295:ITGAM protein, human; D015850:Interleukin-6; D007976:Leupeptins; D018950:Lipopolysaccharide Receptors; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D053181:Caspase 8; D020169:Caspases; D007930:Leucine; C032854:leupeptin; C108192:aloxistatin