title: Tim-3 regulates pro- and anti-inflammatory cytokine expression in human CD14+ monocytes.
abstract: Tim-3 and PD-1 are powerful immunoinhibitory molecules involved in immune tolerance, autoimmune responses, and antitumor or antiviral immune evasion. A current model for Tim-3 regulation during immune responses suggests a divergent function, such that Tim-3 acts synergistically with TLR signaling pathways in innate immune cells to promote inflammation, yet the same molecule terminates Th1 immunity in adaptive immune cells. To better understand how Tim-3 might be functioning in innate immune responses, we examined the kinetics of Tim-3 expression in human CD14+ M/M(Ф) in relation to expression of IL-12, a key cytokine in the transition of innate to adaptive immunity. Here, we show that Tim-3 is constitutively expressed on unstimulated peripheral blood CD14+ monocytes but decreases rapidly upon TLR stimulation. Conversely, IL-12 expression is low in these cells but increases rapidly in CD14+ M/M(Ф) in correlation with the decrease in Tim-3. Blocking Tim-3 signaling or silencing Tim-3 expression led to a significant increase in TLR-mediated IL-12 production, as well as a decrease in activation-induced up-regulation of the immunoinhibitor, PD-1; TNF-α production was not altered significantly, but IL-10 production was increased. These results suggest that Tim-3 has a role as a regulator of pro- and anti-inflammatory innate immune responses.
authors.affiliation: Medical Service, Department of Veterans Affairs, James H. Quillen Veterans Administration Medical Center, Johnson City, Tennessee, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Cheng J
authors.initials: CJ
authors.lastname: Ma
authors.forename: Jia M
authors.initials: JM
authors.lastname: Wang
authors.forename: Xiao J
authors.initials: XJ
authors.lastname: Ji
authors.forename: Xiao Y
authors.initials: XY
authors.lastname: Wu
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Moorman
authors.forename: Zhi Q
authors.initials: ZQ
authors.lastname: Yao
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation; D005786:Gene Expression Regulation; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007113:Immunity, Innate; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D008264:Macrophages / Q000378:metabolism*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009000:Monocytes / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation
chemical_list: D000906:Antibodies; D016207:Cytokines; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C508609:IL10 protein, human; D018950:Lipopolysaccharide Receptors; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D034741:RNA, Small Interfering; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12