Kashkar, Hamid - B 02

TNF is an inflammatory cytokine with pleiotropic effects on various tissues by engaging TNFR1 and TNFR2. Its central role in inflammation has been lately demonstrated by the efficacy of anti-TNF antibodies in controlling a number of different inflammatory diseases including inflammatory bowel disease (IBD). 

CIAP1/2 are ubiquitin (Ub) ligases that control TNF signalling by ubiquitylating RIPK1 leading to TNFR1 induced NFkB activity. Independently, cIAP1/2 also ubiquitylate NIK leading to its degradation and activation of non-canonical NFkB. RIPK1 has been considered as a key regulatory node in TNF-dependent inflammatory diseases and its inhibition is increasingly viewed as a valuable therapeutic option in IBD. In a recent study, we could show that mice lacking cIAP1/2 Ub-ligase activity, RIPK1 kinase activity, and TNFR1 still developed gastrointestinal inflammation suggesting that TNF can induce intestinal inflammation without involving TNFR1 and RIPK1 kinase activity. This project aims to gain molecular insights into the pathophysiologic role of TNF in IBD and will specifically investigate two separate disease conditions in IBD patients including (1) NIK-mediated non-canonical NFkB activity and (2) mutations in XIAP gene. 

We will strongly benefit from newly established transgenic mice in our laboratory and will implement novel drugs specifically targeting NIK and RIPK1 in mouse IBD model. The data obtained will significantly increase our knowledge and will provide important impetus for developing novel therapeutic protocols for IBD.

IBD represents chronical and recurrent disorders caused by complex genetic, immunological and environmental factors. TNF is one of the main drivers of IBD and TNF blockers have been successfully used in IBD patients leading to long-term maintenance of disease remission. However, with nonresponse rates reaching 40% and nondurable remission, medications beyond anti-TNF are required. Here, we will provide novel molecular knowledge and will examine the therapeutic value of emerging novel compounds for IBD treatment.

IAPs, RIPK1, TNF, IBD

• Kashkar H, Pasparakis M. Cell Death Networks Mol. Cell 2025, 85(20):3890-3890.e1.
• Schorn F, Werthenbach JP, Hoffmann M, Daoud M, Stachelscheid J, Schiffmann LM, Hildebrandt X, Lyu SI, Peltzer N, Quaas A, Vucic D, Silke J, Pasparakis M, Kashkar H. cIAPs control RIPK1 kinase activity-dependent and -independent cell death and tissue inflammation. EMBO J. 2023, 42(22):e113614
• Knipper K, Lyu SI, Goebel H, Damanakis AI, Zhao Y, Bruns CJ, Schmidt T, Kashkar H, Quaas A, Schiffmann LM, Popp FC; PANCALYZE Study Group. X-linked inhibitor of apoptosis protein is a prognostic marker for a favorable outcome in three identified subsets in resectable adenocarcinoma of the pancreas J Cancer Res Clin Oncol. 2022, 149(9):5531-5538
• 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

For more information, please check the research site. 

• Center for Molecular Medicine Cologne (CMMC)
• CECAD Cologne
• Institute for Molecular Immunology
• CRC 1218: Mitochondrial regulation of cellular function
• CRC 1403: Cell Death in Immunity, Inflammation and Disease
• CRC 1530: Aufklärung und Targeting pathogener Mechanismen bei B-Zell-Neoplasien
• CRC 1607: Towards immunomodulatory and anti(lymph)angiogenic therapies for age-related blinding eye diseases