Center for Molecular Medicine Cologne

Kashkar, Hamid - B 06

Role of IAPs in TNF-induced vasculature alteration and their therapeutic value in inflammatory diseases


TNF is an inflammatory cytokine that has pleiotropic effects on various tissues. Its central role in inflammation has been lately demonstrated by the efficacy of anti-TNF antibodies in controlling inflammatory diseases. Vascular endothelium represents one of the major targets of TNF which emits diverse responses when exposed to inflammatory conditions. Disease-associated pathogenic vascularization or vascular destruction often occurs in response to excessive TNF. The underlying molecular mechanisms of such diverse vascular responses to TNF have not been yet elucidated. Here we will explore the molecular mechanism of pleiotropic EC responses to TNF and further aim to develop a novel therapeutic concept in order to normalize vessel functions under inflammatory condition. We will in particular focus on inhibitor of apoptosis proteins (IAPs) as key regulating diverge cellular responses to TNF. We will strongly benefit from newly established transgenic mice in our laboratory which harbor EC-specific alteration of IAPs and will utilize experimental disease model systems addressing the function of TNF/IAPs in vessel integrity/function in wound healing and tumor growth. We will implement novel drugs specifically targeting IAPs and their two major downstream targets, RIPK1 and NIK, under disease condition. The data obtained will significantly increase our knowledge about the vascular responses to inflammatory disease conditions and will provide important impetus for developing novel therapeutic protocols for inflammatory disorders.

Clinical Relevance

Inflammatory diseases affect approximately 7.6–9.4% of the world population. The majority of these diseases involves vascular endothelium leading to multi-organ involvement. Anti-TNF therapy can efficiently reduce tissue damage and improve vascular function. This project aims to exploit the recent in-depth molecular knowledge on TNF signaling and evaluate emerging novel compounds which interfere with TNF-signaling as new therapeutic options for inflammatory disorder.


  • Transgenic mouse model
  • in vitro angiogenesis assay
  • therapeutic evaluation of new compound
Figure 1
  • Daoud M, Broxtermann PN, Schorn F, Werthenbach JP, Seeger JM, Schiffmann LM, Brinkmann K, Vucic D, Tüting T, Mauch C, Kulms D, Zigrino P, Kashkar H. XIAP promotes melanoma growth by inducing tumour neutrophil infiltration EMBO Rep 2022 23(6), e53608
  • Schiffmann LM, Werthenbach JP, Heintges-Kleinhofer F, Seeger JM, Fritsch M, Günther SD, Willenborg S, Brodesser S, Lucas C, Jüngst C, Albert MC, Schorn F, Witt A, Moraes CT, Bruns C, Pasparakis M, Krönke M, Eming SA, Coutelle O, Kashkar H. Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth. Nat. Commun. 2020, 11(1):3653
  • Fritsch M, Günther SD, Schwarzer R, Albert MC, Schorn F, Werthenbach JP, Schiffmann LM, Stair N, Stocks H, Seeger JM, Lamkanfi M, Krönke M, Pasparakis M, Kashkar H.Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature 2019, 575(7784):683-687
  • Schiffmann LM, Fritsch M, Gebauer F, Günther SD, Stair NR, Seeger JM, Thangarajah F, Dieplinger G, Bludau M, Alakus H, Göbel H, Quaas A, Zander T, Hilberg F, Bruns CJ, Kashkar H*, Coutelle O*. Tumour-infiltrating neutrophils counteract anti-VEGF therapy in metastatic colorectal cancer. Br J Cancer. 2019, 120(1):69-78 *equal contribution
  • Witt A, Seeger JM, Coutelle O, Zigrino P, Broxtermann P, Andree M, Brinkmann K, Jüngst C, Schauss AC, Schüll S, Wohlleber D, Knolle P, Krönke M, Mauch C, Kashkar H. IAP antagonization induces inflammatory destruction of vascular endothelium EMBO Rep. 2015, 16:719-727
  • Coutelle O, Schiffmann LM, Liwschitz M, Brunold M, Goede V, Hallek M, Kashkar H*, Hacker UT*. Dual targeting of Angiopoetin-2 and VEGF potentiates effective vascular normalization without inducing empty basement membrane sleeves in xenograft tumors. Br J Cancer 2015, 112:495-503 *equal contribution
  • Coutelle O, Hornig-Do HT, Witt A, Andree M, Schiffmann LM, Liwschitz M, Seeger JM, Piekarek M, Brinkmann K, Hallek M, Krönke M, Trifunovic A, Eming SA, Wiesner RJ, Hacker UT, Kashkar H. Embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing EMBO Mol. Med. 2014, 6:624-639
Prof. Dr. Hamid Kashkar CMMC Cologne
Prof. Dr. Hamid Kashkar

Institute for Molecular Immunology | CECAD Research Center

CMMC - PI - B 06
Head - CMMC Cell Sorting Facility

+49 221 478 84091

+49 221 478 32002

Institute for Molecular Immunology | CECAD Research Center

Joseph-Stelzmann-Str. 26

50931 Cologne

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Curriculum Vitae (CV)

Publications on PubMed

Publications - Hamid Kashkar

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Group Members

Jens Michale Seeger, Mila Daoud, Paul Werthenbach, Alina Farid, Johanna Stachelscheid, Melanie Fritsch, Noëlle Sieg
PhD students
Bessarta Thaqi, Larissa Groth, Hossein Hozhabri
Master students
Daniela Hahn, Ben Lengert
Medical students
Patrick Glaser, Marius Rühl
Maureen Menning, Ali Manav, Tanja Roth