Head


Falk Weih
Falk Weih

Staff Scientists

Debra Weih (histology)

Postdocs

Ronny Hänold

Agnes Lovas

Marc Riemann

PhD Students

Desheng Hu

Branislav Krljanac

Iwona Powolny

Diploma Students

Christian Günschmann

Lars Wiechert

Technicians

Elke Meier

Simone Tänzer (Flow cytometry)



Weih Laboratory

Immunology

The NF-κB signal transduction pathway in development and dysfunction of the immune system

The Rel/NF-κB transcription factors play a pivotal role in immune responses, inflammation/autoimmunity, the regulation of apoptosis, and in cancer. With the help of genetically altered mouse models we are analyzing the NF-κB signaling pathway in both normal development and pathological alterations of the immune system, focusing on the recently described alternative activation pathway. One of our goals is a better understanding of NF-κB function in age-related immune deficiencies and disease.

 

Activation of NF-κB by the alternative (left)

Figure 1. Activation of NF-κB by the alternative (left) and the classical pathway (right). Signaling through TNFR, IL-1R, or Toll-like receptors (TLR) activates the classical NF-κB pathway involving predominantly the β and γ subunits of the IKK complex. Nuclear translocation and DNA-binding of p50-RelA heterodimers is accomplished through IκBα phosphorylation and ubiquitin-dependent proteasomal degradation. Membrane-bound LTα1β2, CD40, and BAFF, on the other hand, activate via their respective receptors the kinases NIK and IKKα. Phosphorylation of p100 results in the processing of the precursor to the p52 subunit and nuclear accumulation of p52-RelB heterodimers. There is significant cross talk since signaling through the LTβR, for instance, also results in the induction of RelA complexes. It is believed that the two pathways activate distinct sets of genes.

 

 

 

 

 

 

Projects

  • Regulation of lymphoid organ development by the NF-κB signaling pathway
  • Development and function of natural killer T cells and γδ T cells
  • Regulation of early B cell development by NF-κB
  • Tertiary lymphoid organs in atherosclerosis
  • Role of NF-κB in neurodegeneration and neuroprotection

 

Recent selected publications

  • Maruyama T, Fukushima H, Nakao K, Shin M, Yasuda H, Weih F, Doi T, Aoki K, Alles N, Ohya K, Hosokawa R, Jimi E (2009) Processing of the NF-kappaB2 Precursor, p100, to p52 is Critical for RANKL-Induced Osteoclast Differentiation. J Bone Miner Res [Epub ahead of print]
  • Soysa NS, Alles N, Weih D, Lovas A, Mian AH, Shimokawa H, Yasuda H, Weih F, Jimi E, Ohya K, Aoki K (2009) The Pivotal Role of the Alternative NF-kappaB Pathway in Maintenance of Basal Bone Homeostasis and Osteoclastogenesis. J Bone Miner Res [Epub ahead of print]
  • Lötzer K, Döpping S, Connert S, Gräbner R, Spanbroek R, Lemser B, Beer M, Hildner M, Hehlgans T, van der Wall M., Mebius R E, Lovas A, Randolph GJ, Weih F* and Habenicht A.J.R. * (2009) Mouse aorta smooth muscle cells differentiate into lymphoid tissue organizer-like cells upon combined TNFR1/LTβR NF-κB signaling. Arterioscler Thromb Vasc Biol [in press]
    *Equal contribution
  • Gräbner R, Lötzer K, Döpping S, Hildner M, Radke D, Beer M, Spanbroek R, Lippert B, Reardon DR, Getz GS, Fu YK,T. Hehlgans T, Mebius RE, van der Wall M, Kruspe D, Englert C, Lovas A, Hu D, Randolph GJ, Weih F, Habenicht AJR (2009) Lymphotoxin β receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE -/- mice. J Exp Med 206, 233-48.
  • Lovas A, Radke D, Albrecht D, Yilmaz ZB, Möller U, Habenicht AJR, Weih F (2008) Differential RelA- and RelB-dependent gene transcription in LTβR-stimulated mouse embryonic fibroblasts. BMC Genomics 9, 606.
  • Dos Santos NR, Williame M, Gachet S, Cormier F, Janin A, Weih D, Weih F, Ghysdael J (2008) RelB-dependent stromal cells promote T-cell leukemogenesis. PLoS ONE. 3, e2555. [PubMed]
  • Guo F, Tänzer S, Busslinger M, Weih F (2008) Lack of NF-κB2/p100 causes a RelB-dependent block in early B lymphopoiesis. Blood. 112, 551-559. [PubMed]
  • Vallabhapurapu S, Powolny-Budnicka I, Riemann M, Schmid RM, Paxian S, Pfeffer K, Körner H, Weih F (2008) Rel/NF-κB family member RelA regulates NK1.1- to NK1.1+ transition as well as IL-15-induced expansion of NKT cells. Eur J Immunol 38, 3508-3519.
  • Balogh P, Balázs M, Czömpöly T, Weih DS, Arnold HH, Weih F (2007) Distinct roles of lymphotoxin-β signaling and the homeodomain transcription factor Nkx2.3 in the ontogeny of endothelial compartments in spleen. Cell Tissue Res. 328, 473-486. [PubMed]
  • Freyschmid EJ, Mathias CB, MacArthur DH, Laouar A, Narasimhaswamy M, Weih F, Oettgen HC (2007) Skin inflammation in RelB-/- mice leads to defective immunity and impaired viral clearance of vaccinia virus. J Allergy Clin Immunol. 119, 671-679. [PubMed]
  • Guo F, Weih D, Meier E, Weih F (2007) Constitutive alternative NF-κB signaling promotes marginal zone B cell development but disrupts the marginal sinus and induces HEV-like structures in the spleen. Blood. 110, 2381-2389. [PubMed]
  • Lo JC, Basak S, James ES, Quiambo RS, Kinsella MC, Alegre ML, Weih F, Franzoso G, Hoffmann A, Fu YX (2006) Coordination between NF-κB family members p50 and p52 is essential for mediating LTβR signals in the development and organization of secondary lymphoid tissues. Blood. 107, 1048-1055. [PubMed]
  • Zhang W, Potrovita I, Tarabin V, Herrmann O, Beer V, Weih F, Schneider A, Schwaninger M (2005) Neuronal activation of NF-κB contributes to cell death in cerebral ischemia. J Cereb Blood Flow Metab. 25, 30-40. [PubMed]
  • Sivakumar V, Hammond KJ, Howells N, Pfeffer K, Weih F (2003) Differential requirement for Rel/nuclear factor κB family members in natural killer T cell development. J Exp Med. 197, 1613-1621. [PubMed]
  • Weih F, Caamaño J (2003) Regulation of secondary lymphoid organ development by the nuclear factor-κB signal transduction pathway. Immunol Rev. 195, 91-105. [PubMed]
  • Yilmaz ZB, Weih DS, Sivakumar V, Weih F (2003) RelB is required for Peyer's patch development: differential regulation of p52-RelB by lymphotoxin and TNF. EMBO J. 22, 121-130. [PubMed]
  • Weih DS, Yilmaz ZB, Weih F (2001) Essential role of RelB in germinal center and marginal zone formation and proper expression of homing chemokines. J Immunol. 167, 1909-1919. [PubMed]
  • Schneider A, Martin-Villalba A, Weih F, Vogel J, Wirth T, Schwaninger M (1999) NF-κB is activated and promotes cell death in focal cerebral ischemia. Nat Med. 5, 554-559. [PubMed]
  • Weih F, Durham SK, Barton DS, Sha WC, Baltimore D, Bravo R (1997) p50-NF-κB complexes partially compensate for the absence of RelB: severely increased pathology in p50-/-relB-/- double-knockout mice. J Exp Med. 185, 1359-1370. [PubMed]
  • Weih F, Carrasco D, Durham SK, Barton DS, Rizzo CA, Ryseck RP, Lira SA, Bravo R (1995) Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-κB/Rel family. Cell. 80, 331-340. [PubMed]

 

Last update: September 16, 2008
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