Dampening cytokine production

Although TRAIL receptor (TRAIL-R) signaling is associated with apoptosis induction in vitro, the in vivo function of TRAIL-R is not well understood. In Immunity, Winoto and colleagues show that the innate immune response to certain pathogens is enhanced in TRAIL-R-deficient mice. Increased clearance of mouse cytomegalovirus from the spleen was associated with increased IL-12, IFN-α and IFN-β production by dendritic cells and macrophages. Likewise, 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 cells. Specifically, TRAIL-R deficiency affected re-expression of IκBα at later times after TLR signaling. These data show TRAIL-R signaling normally negatively regulates the cytokine response of the innate immune system. JDKW

Immunity 21, 877–889 (2004)

Targeting MyD88

Transforming growth factor (TGF) is a potent anti-inflammatory cytokine, but it is uncertain how this cytokine might modulate inflammatory signals from the pathogen-sensing TLRs. In the Journal of Biological Chemistry, Naiki et al. find that TGF-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 their degradation. In contrast, TGF-β1 did not affect the alternate signaling pathway of TLR4 that involves the adaptors TRIF and TRAM. Understanding the control of TLR signaling pathway by TGF-β1 may help the rational design of therapy for inflammation. PTL

J. Biol. Chem. 10.1074/jbc.C400503200 (28 December 2004)

EphB6 effects

T cells express the cell surface tyrosine kinase receptor EphB6, but its physiological function is unclear. In the Journal of Clinical Investigation, Wu and colleagues generated EphB6-deficient mice to analyze the in vivo function of EphB6. Cytokine production and proliferation by EphB6-deficient T cells was defective in vitro, whereas delayed-type skin hypersensitivity was compromised and experimental autoimmune 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 after activation. The absence of EphB6 abrogated Zap70 phosphorylation and activation of other 'downstream' members of the raft-residing TCR signalosome, such as LAT and SLP-76. Thus, EphB6 is critical for TCR signaling and T cell function. JDKW

J. Clin. Invest. 114, 1762–1773 (2004)

Uniquely pDC

Plasmacytoid dendritic cells (pDCs) are functionally distinct from myeloid DCs (mDCs). Although pDCs are found in various extralymphoid tissues during inflammation, they do not respond to inflammatory chemokines. In the Journal of Immunology Zabel et al. show that circulating pDCs uniquely express a chemokine receptor known as chemokine-like receptor 1 (CMKLR1, also known as ChmeR23 or DEZ) that distinguishes them from mDCs. The ligand for CMKLR1, chemerin, was detectable in human sera. The mRNA of chemerin was also present in many tissues, including the liver, pancreas and adrenal glands. Chemerin attracted blood pDCs but not mDCs. Because active chemerin requires proteolytic processing, the presence of these enzymes at sites of inflammation and tissue damage may serve to recruit pDCs. PTL

J. Immunol. 174, 244–251 (2005)

HIV susceptibility locus

The CC chemokine CCL31L, also called MIP-1αP, has a suppressive function in HIV infection. CCL31L is the main ligand for the HIV co-receptor CCR5. In Science, Gonzalez et al. show 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 copies of CCL3L1. Statistical analyses also linked higher gene copy numbers with a lessened risk of HIV acquisition and reduced disease progression once the virus was acquired. Such variation in CCL3L1 'dosage' constitutes a greater risk factor than the previously identified CCR5 polymorphisms. LAD

Science 10.1126/science.1101160 (6 January 2005)

Essential CARM1

CARM1, a member of the arginine methyltransferase family, can form a complex with p300, CBP and SRC-2, which function as coactivators of NF-κB. In the EMBO Journal, Covic et al. used CARM1-deficient cells to investigate whether CARM1 is required for NF-κB-dependent gene activation. CARM1 deficiency impaired expression of a subset of NF-κB-dependent genes. CARM1 physically interacted with the NF-κB subunit p65 and the coactivator p300. Mechanistically, CARM1 augmented coactivation of NF-κB-dependent gene activation by p300 and SRC-2 and enhanced p65 recruitment to κB sites contained in histone 3 (R17)–methylated promoters. The enzymatic activities of both CARM1 and p300 were essential for the observed synergistic enhancement of NF-κB-dependent transcription. These data suggest CARM1 functions as a promoter-specific coactivator of NF-κB-dependent gene expression. JDKW

EMBO J. (16 December 2004) 10.1038/sj.emboj.7600500

Regulating NEMO

NOD2 has a complex function in NF-κB activation in response to inflammatory mediators. NOD2 and RIP2 interact with IκB kinase (IKK) to target the inhibitor IκB for degradation. But Crohn disease, an inflammatory disorder, is associated with certain NOD2 mutations, suggesting NOD2 has both positive and negative functions. In Current Biology, Cantley and colleagues show NOD2 and RIP2 induce ubiquitinylation of NEMO, the regulatory subunit of IKK. This modification, a polyubiquitinylation of lysine 63 (K63), did not lead to NEMO degradation. Instead, RIP2-mediated NEMO ubiquitinylation activated NF-κB, as shown by altering expression of the K63 deubiquitinase CYLD. 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.