title: Cripto-1 modulates macrophage cytokine secretion and phagocytic activity via NF-κB signaling.
abstract: Cripto-1 is an oncogenic protein belonging to the epidermal growth factor–Cripto-1/FRL-1/Cryptic family. It has important roles in tumor formation and metastasis, but its effects on the immune system are unclear. In the present study, we investigated the effects of Cripto-1 overexpression on macrophage activities and examined the underlying mechanisms. A cell line stably overexpressing Cripto-1 was developed. The culture supernatant from this cell line was collected and used to condition macrophages (RAW264.7, THP-1, and primary mouse macrophages) for various times. Exposure to this supernatant significantly increased the mRNA and protein expression levels of the anti-inflammatory cytokine interleukin (IL)-10 and of three pro-inflammatory cytokines (tumor necrosis factor-α, IL-6, and IL-1β), but did not affect the expression of transforming growth factor-β, another anti-inflammatory cytokine. Exposure to this supernatant also enhanced macrophage phagocytosis of chicken erythrocytes and yeast cells. Similar effects were observed in macrophages stimulated with purified Cripto-1 protein. Mechanistic experiments revealed that Cripto-1 activated nuclear factor (NF)-κB signaling by inducing IκB kinase phosphorylation and p65 nuclear translocation. Pretreatment with ammonium pyrrolidine dithiocarbamate, a specific NF-κB inhibitor, inhibited Cripto-1-induced cytokine secretion and phagocytosis of macrophages. Taken together, our present findings suggest that Cripto-1 enhances macrophage phagocytic activity and upregulates the production of anti- and pro-inflammatory cytokines via the NF-κB signaling pathway.
authors.forename: Dong-mei
authors.initials: DM
authors.lastname: Zhang
authors.forename: Yong-Li
authors.initials: YL
authors.lastname: Bao
authors.forename: Chun-Lei
authors.initials: CL
authors.lastname: Yu
authors.forename: Yi-meng
authors.initials: YM
authors.lastname: Wang
authors.forename: Zhen-Bo
authors.initials: ZB
authors.lastname: Song
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D011759:Pyrrolidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013859:Thiocarbamates / Q000494:pharmacology
chemical_list: D016207:Cytokines; D058851:GPI-Linked Proteins; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011759:Pyrrolidines; C070636:TDGF1 protein, human; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid