Dampening Cytokine Production HIV Susceptibility Locus Targeting
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RESEARCH HIGHLIGHTS Dampening cytokine production circulating pDCs uniquely express a chemokine receptor known as che- mokine-like receptor 1 (CMKLR1, also known as ChmeR23 or DEZ) that Although TRAIL receptor (TRAIL-R) signaling is associated with distinguishes them from mDCs. The ligand for CMKLR1, chemerin, was apoptosis induction in vitro, the in vivo function of TRAIL-R is not detectable in human sera. The mRNA of chemerin was also present in well understood. In Immunity, Winoto and colleagues show that the many tissues, including the liver, pancreas and adrenal glands. Chemerin innate immune response to certain pathogens is enhanced in TRAIL- attracted blood pDCs but not mDCs. Because active chemerin requires R-deficient mice. Increased clearance of mouse cytomegalovirus proteolytic processing, the presence of these enzymes at sites of inflam- from the spleen was associated with increased IL-12, IFN-α and mation and tissue damage may serve to recruit pDCs. PTL IFN-β production by dendritic cells and macrophages. Likewise, J. Immunol. 174, 244–251 (2005) Toll-like receptor 2 (TLR2), TLR3 and TLR4 stimulation, along with mycobacterial stimulation, enhanced cytokine production and also induced upregulation of TRAIL expression by these innate immune HIV susceptibility locus cells. Specifically, TRAIL-R deficiency affected re-expression of IκBα at later times after TLR signaling. These data show TRAIL-R The CC chemokine CCL31L, also called MIP-1αP, has a signaling normally negatively regulates the cytokine response of the suppressive function in HIV infection. CCL31L is the main ligand innate immune system. JDKW for the HIV co-receptor CCR5. In Science, Gonzalez et al. show Immunity 21, 877–889 (2004) CCL3L1 copy numbers vary among diverse human populations and link this variation with susceptibility to HIV infection. HIV- positive groups were over-represented by individuals having fewer Targeting MyD88 copies of CCL3L1. Statistical analyses also linked higher gene copy numbers with a lessened risk of HIV acquisition and reduced Transforming growth factor (TGF) is a potent anti-inflammatory disease progression once the virus was acquired. Such variation cytokine, but it is uncertain how this cytokine might modulate in CCL3L1 ‘dosage’ constitutes a greater risk factor than the inflammatory signals from the pathogen-sensing TLRs. In the http://www.nature.com/natureimmunology previously identified CCR5 polymorphisms. LAD Journal of Biological Chemistry, Naiki et al. find that TGF- Science (6 January 2005) doi:10.1126/science.1101160 β1 inhibits TLR2-, TLR4- and TLR5-mediated activation of the transcription factor NF-κB and hence the production of inflammatory cytokines such as TNF. TGF-β1 promoted the direct ubiquitination of the TLR adaptor protein MyD88, leading to Essential CARM1 their degradation. In contrast, TGF-β1 did not affect the alternate CARM1, a member of the arginine methyltransferase family, can form signaling pathway of TLR4 that involves the adaptors TRIF and a complex with p300, CBP and SRC-2, which function as coactivators TRAM. Understanding the control of TLR signaling pathway by TGF- of NF-κB. In the EMBO Journal, Covic et al. used CARM1-deficient β1 may help the rational design of therapy for inflammation. PTL cells to investigate whether CARM1 is required for NF-κB-dependent J. Biol. Chem. (28 December 2004) doi:10.1074/ gene activation. CARM1 deficiency impaired expression of a sub- jbc.C400503200 set of NF-κB-dependent genes. CARM1 physically interacted with the NF-κB subunit p65 and the coactivator p300. Mechanistically, 2005 Nature Publishing Group Group 2005 Nature Publishing CARM1 augmented coactivation of NF-κB-dependent gene activa- © EphB6 effects tion by p300 and SRC-2 and enhanced p65 recruitment to κB sites T cells express the cell surface tyrosine kinase receptor EphB6, but its contained in histone 3 (R17)–methylated promoters. The enzymatic physiological function is unclear. In the Journal of Clinical Investigation, activities of both CARM1 and p300 were essential for the observed Wu and colleagues generated EphB6-deficient mice to analyze the in synergistic enhancement of NF-κB-dependent transcription. These vivo function of EphB6. Cytokine production and proliferation by data suggest CARM1 functions as a promoter-specific coactivator of EphB6-deficient T cells was defective in vitro, whereas delayed-type NF-κB-dependent gene expression. JDKW skin hypersensitivity was compromised and experimental autoim- EMBO J. (16 December 2004) doi:10.1038/sj.emboj.7600500 mune encephalitis induction was less severe in vivo. In contrast, humoral immune responses were unaffected in EphB6-deficient mice. In wild- type thymocytes, EphB6 ‘co-capped’ with T cell receptor (TCR) and rafts Regulating NEMO after activation. The absence of EphB6 abrogated Zap70 phosphoryla- NOD2 has a complex function in NF-κB activation in response tion and activation of other ‘downstream’ members of the raft-residing to inflammatory mediators. NOD2 and RIP2 interact with IκB TCR signalosome, such as LAT and SLP-76. Thus, EphB6 is critical for kinase (IKK) to target the inhibitor IκB for degradation. But Crohn TCR signaling and T cell function. JDKW disease, an inflammatory disorder, is associated with certain J. Clin. Invest. 114, 1762–1773 (2004) NOD2 mutations, suggesting NOD2 has both positive and negative functions. In Current Biology, Cantley and colleagues show Uniquely pDC NOD2 and RIP2 induce ubiquitinylation of NEMO, the regulatory subunit of IKK. This modification, a polyubiquitinylation of Plasmacytoid dendritic cells (pDCs) are functionally distinct from lysine 63 (K63), did not lead to NEMO degradation. Instead, myeloid DCs (mDCs). Although pDCs are found in various extralym- RIP2-mediated NEMO ubiquitinylation activated NF-κB, as phoid tissues during inflammation, they do not respond to inflamma- shown by altering expression of the K63 deubiquitinase CYLD. tory chemokines. In the Journal of Immunology Zabel et al. show that Ubiquitinylated NEMO might then act as a scaffold to integrate the various NF-κB activating signals. LAD Curr. Biol. 14, 2217–2227 (2004) Written by Laurie A. Dempsey, Peter T. Lee and Jamie D.K. Wilson. NATURE IMMUNOLOGY VOLUME 6 NUMBER 2 FEBRUARY 2005 133.