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NATURE REVIEWS | IMMUNOLOGY VOLUME 3 | JANUARY 2003 | 9

The inflammatory response tolipopolysaccharide (LPS) is crucialfor protecting the host against patho-genic bacteria, but excessive cytokineproduction can be harmful and, insome cases, fatal if LPS-inducedshock occurs. Therefore, LPS sig-nalling, through the LPS receptorToll-like receptor 4 (TLR4), needs tobe controlled tightly. But, how is thisachieved? Two papers in Immunitynow indicate a central role for sup-pressor of cytokine signalling 1(SOCS1) in the negative regulation ofLPS signalling.

SOCS1 was identified initially as anegative regulator of signallingdownstream of cytokines. However,SOCS1 is expressed by macrophagesafter stimulation with LPS. This fact,combined with the observation thatSocs1−/− mice develop inflammatoryorgan disease, led the authors to askwhether SOCS1 downmodulates LPSsignalling.

Both groups looked at the effect ofSOCS1 deficiency on the response toLPS. Nakagawa et al. showed thatSocs1−/− mice (pre-disease onset) andSocs1+/− mice are hyper-responsive toLPS and are sensitive to LPS-inducedlethality. Macrophages from thesemice produced increased amounts ofthe pro-inflammatory cytokinestumour-necrosis factor (TNF) andinterleukin-12 (IL-12). Kinjyo et al.also investigated the response of

Socs+/– mice to LPS. First, they crossedthese mice onto an interferon-γ(IFN-γ)-deficient background toeliminate any effect of SOCS1 onIFN-γ signalling. IFN-γ-deficientSocs1−/− and IFN-γ-deficient Socs1+/−

mice were more sensitive than IFN-γ-deficient Socs1+/+ mice to LPS, andmacrophages from these mice pro-duced high levels of TNF and nitricoxide in response to LPS.

When wild-type mice are treatedwith a low dose of LPS, they are pro-tected from the effects of a higher,potentially fatal, dose when adminis-tered later on. This phenomenon isknown as ‘LPS tolerance’. Is SOCS1-mediated downregulation of LPS sig-nal transduction important for thisprotective mechanism? These studiesshowed that a similar pre-treatment ofSocs1−/− mice and Socs1−/− macro-phages with LPS did not protect themfrom a subsequent higher dose, indi-cating that SOCS1 is required forLPS tolerance.

To find out how SOCS1 regulatesthe response to LPS, both groups over-expressed SOCS1 in a macrophage cellline. SOCS1-overexpressing macro-phages produced little nitric oxide andTNF in response to LPS, and theactivities of signal transducer andactivator of transcription 1 (STAT1)and nuclear factor-κB (which are bothrequired for the generation of nitricoxide) were reduced in these cells.

These studies show that, in addi-tion to a central role in controllingadaptive immune responses down-stream of cytokines, SOCS1 cansuppress TLR4 signalling directlyand modulate the innate immuneresponse.

Jenny Buckland

References and linksORIGINAL RESEARCH PAPERS Kinjyo, I. et al.SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity 17,583–591 (2002) | Nakagawa, R. et al. SOCS-1participates in negative regulation of LPSresponses. Immunity 17, 677–687 (2002)FURTHER READING Medzhitov, R. Toll-likereceptors and innate immunity. Nature Rev.Immunol. 1, 135–146 (2002)

SOCS1 and the innateimmune response

M A C R O P H A G E S IN BRIEF

IFN-γ represses IL-4 expresssion via IRF-1 and IRF-2.Elser, B. et al. Immunity 17, 703–712 (2002)

On the basis of patterns of cytokine expression, CD4+ T cells can be divided into T

H1 and T

H2 cells. IFN-γassists T

H1-cell

development, but until now, a direct effect of IFN-γon theexpression of T

H2 cytokines has not been shown. This study

shows that IFN-γ represses the expression of IL-4, a crucial TH

2-inducing cytokine, by inducing the expression of interferonregulatory factor 1 (IRF1) and IRF2, which bind to sites in theIL-4 promoter and suppress its activity.

A signal peptide derived from hsp60 binds HLA-E andinterferes with CD94/NKG2A recognition.Michaëlsson, J. et al. J. Exp. Med. 196, 1403–1414 (2002)

Interaction of HLA-E — a non-classical MHC molecule thatpresents mainly peptides derived from other MHC class Imolecules — with the inhibitory NK-cell receptor CD94–NKG2Aprevents the activation of NK cells. This study shows that HLA-Ecan present a peptide from HSP60 (the expression of which isupregulated in stressed cells), which prevents the complex frombeing recognized by CD94–NKG2A. A greater number of suchcomplexes are likely to be expressed by stressed cells, which couldblock inhibitory signalling and allow NK cells to kill stressed cells.

Non-T-cell activation linker (NTAL): a transmembraneadaptor protein involved in immunoreceptor signalling.Brdicka, T. et al. J. Exp. Med. 196, 1617–1626 (2002)

Linker for activation of T cells (LAT) is an important componentof TCR signalling pathways. However, B cells and natural killer(NK) cells do not express LAT. Do they express a LAT-likemolecule? Here, Brdicka et al. identify a new transmembraneadaptor protein that is structurally and evolutionarily related toLAT, known as non-T-cell activation linker (NTAL), which isexpressed by B cells, NK cells, monocytes and mast cells, andwhich seems to function in a LAT-like manner.

Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-β promoter in the Toll-like receptor signaling.Yamamoto, M. et al. J. Immunol. 169, 6668–6672 (2002)

Although the TIR-domain-containing adaptor TIRAP wasthought to mediate signalling from TLRs through the MYD88-independent pathway, this was shown recently not to be the case.Now,Yamamoto et al. report the identification of a new adaptor,TIR-domain-containing adaptor inducing IFN-β (TRIF). Studiesusing a dominant-negative form of TRIF show that it is involved inTLR signalling, particularly in the MYD88-independent pathway.

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