Flowchart: Preparation: Rip2

Text Box:  Mdp

Inflammratory Disease

Text Box: IL-1beta

Text Box: Rip2

Text Box: IL-6



Loss-of-Function Deletion of the Steroid Receptor Coactivaor-1 Gene in Mice Reduces Estrogen Effect on the Vascular Injury Response.

     Yuan Y, Xu J.


J Leukoc Biol. 2007 Apr 2; [Epub ahead of print]Click here to read  Links

MDP-induced interleukin-1{beta} processing requires Nod2 and CIAS1/NALP3.

     Pan Q, Mathison J, Fearns C, Kravchenko VV, Correia JD, Hoffman HM, Kobayashi KS, Bertin J, Grant EP, Coyle AJ, Sutterwala FS, Ogura Y, Flavell RA, Ulevitch RJ.

*Department of Immunology, The Scripps Research Institute, La Jolla, California, USA; Ludwig Institute of Cancer Research and University of California at San Diego, La Jolla, California, USA; Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, Massachusetts, USA; Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA; and Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.

Nucleotide-binding oligomerization domain (Nod)2 is a sensor of muramyl dipeptides (MDP) derived from bacterial peptidoglycan. Nod2 also plays a role in some autoinflammatory diseases. CIAS1/Natch domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NALP3) has been suggested to be sufficient for MDP-dependent release of mature IL-1beta, but the role of Nod2 in this process is unclear. Using mice bearing selective gene deletions, we provide in vitro and in vivo data showing that MDP-induced IL-1beta release requires Nod2 and CIAS1/NALP3 as well as receptor-interacting protein-2 (Rip2), apoptosis-associated speck-like protein containing a caspase activation and recruitment domain, and caspase-1. In contrast, MDP-dependent IL-6 production only requires Nod2 and Rip2. Together, our data provide a new understanding of this important pathway of IL-1beta production and allow for further studies of the role of these proteins within the broader context of inflammatory disease.

PMID: 17403772 [PubMed - as supplied by publisher]

Biochem J. 2007 Mar 9; [Epub ahead of print]Click here to read  Links

Molecular mechanisms involved in the regulation of cytokine production by muramyl dipeptide.

     Windheim M, Lang C, Peggie M, Cummings L, Cohen P.

Muramyl dipeptide (MDP), a component of peptidoglycan, interacts with NOD2 stimulating the NOD2/RIP2 complex to activate signaling pathways important for anti-bacterial defence. Here we demonstrate that the protein kinase activity of RIP2 has two functions, namely to limit the strength of downstream signaling and to stabilise the active enzyme. Thus pharmacological inhibition of RIP2 kinase with either SB 203580 or PP2 induces a rapid and drastic decrease in the level of the RIP2 protein, which may explain why these RIP2 inhibitors block MDP-stimulated downstream signaling and the production of IL-1beta and TNFalpha. We also show that RIP2 induces the activation of the protein kinase TAK1, that a dominant negative mutant of TAK1 inhibits RIP2-induced activation of JNK and p38alpha MAPK, and that signaling downstream of NOD2 or RIP2 is reduced by the TAK1 inhibitor 5Z-7-oxo-zeaenol or in TAK1-deficient cells. We also show that MDP activates ERK1/ERK2 and p38alpha MAPK in human PBMC and that both MAP kinases and TAK1 activity are required for MDP-induced production of IL-1beta and TNFalpha in these cells. Taken together, our results indicate that the MDP-NOD2/RIP2 and LPS-TLR4 signaling pathways converge at the level of TAK1 and that many subsequent events that lead to the production of pro-inflammatory cytokines are common to both pathways.

PMID: 17348859 [PubMed - as supplied by publisher