Research

Chronic Inflammation and Carcinogenesis dendritic cell biology, sphingolipids and chemokinesin vitro and in vivo

Heinfried H. Radeke (group leader),

Introduction

Infiltrates of mononuclear cells represent the hallmark of chronic inflammation. Following tissue injury cells of the innate and adaptive immune system invade the respective area through their interaction with adhesion molecules and chemotactic factors, such as bacterial components, lipids, complement fragments andchemokines. Moreover, chronic inflammation is specifically characterized by pathological homing, leading to tertiary lymphoid structures.The interaction of the injurious agent and local cells with the professional immune system will have a decisive influence on the transition from acute to chronic inflammation, a process finally destroying vital organ function. Chronic inflammatory processes always include futile repair processes including cell protective mechanisms that eventually will support a cancerogenic transformation. Our research interest focuses on different aspects of chronicity and cancerogenesisin relevant diseases models and human patients and the evaluation of pharmacological targets.

Figure 1. Projects of the group are centered around the role of dendritic and T cells in chronic inflammation and cancerogenesis (click on project items for details).

Topics

(1) Chronic inflammation and chemokines
Nadine Ogrissek (Oliver Giegold)

During an immune response certain chemokines are especially important for extravasation of T cells into inflamed tissue. An upregulated inflammatory chemokine receptor signaling is known to be involved in the pathogenesis of autoimmunity. Therefore these receptors are promising targets for the treatment of chronic inflammatory disorders like type-1-diabetes, multiple sclerosis or psoriasis. However, single chemokine receptor antagonists or anti-chemokine antibodies often missed final approval for a clinic application. Our recent investigations contributed to the understanding of the underlying reasons, e.g. redundancy, systemic application and heterologous interaction of homing and inflammatory chemokines. Thus, we decided to develop a cell-based therapy for chronic inflammation with a treatment that is not only based on the effect of chemokine receptor antagonists combinations, but moreover on a localized, and “on demand“ release by means of TCR-activation-dependent antagonist expression.Our methodological arsenal encompasses conditional lentiviral vector cloning, lymphocyte transduction, FACS sorting and dynamic flow chamber assays.


(2) S1P, sphingolipid enzymes and Interleukin-33
Annika Wagner, Dominik Bergis, Valentin Kassis

Sphingolipids have evolved from their limited role as membrane proteins. Sphingolipid metabolites, especially the bioactive sphingosine-1-phosphate (S1P), play an important role in autoimmune diseases and inflammation. The control of the S1P concentrations with respect to phosphorylating enzymes (sphingosine kinase 1 (SphK1) and SphK2) or degrading enzymes (S1P lyase and S1P phosphatases) is of prominent interest. On the other hand dendritic cells are crucial for inflammatory responses. Therefore, one of the three sphingolipid projects is focused on the regulation of the S1P degrading enzymes, e.g. S1P lyase, in murine dendritic cells. Recently we described a modulating effect of extracellular S1Plimited to dendritic cell IL-12p35 expression. Currently, we analyse the role of intracellular S1P on dendritic cell signaling using conditional sgpl1 knockout strategy and siRNA(Olga Arlt). Furthermore we are interested in interleukin-33, one of the endogenous “alarmins”. Processed differentially during apoptotic and necrotic conditions and depending on its soluble receptor it may act in a pro- or an anti-inflammatory manner. In detail we study the influence of the IL-33/ST2 and sphingolipid pathway in different human diseases:


(3) Chronic Inflammation and cancerogenesis
Martina Herrero SanJuan, (Coop: Cornelia Richter, University Dresden; Ugur Sahin and Kerstin Reuter, TRON, Mainz)

On the background of the simple enigma how dendritic cells may either prevent or support chronic inflammation dependent cancerogenesis we have been investigating differential TLR signaling pathways leading to either IL-12 or IL-23. Among other factors the balance between IL-12 and IL-23 modulates chronic colon inflammation and colon cancer. Based on previous mouse colitis studies we now established a colitis associated colon cancer model. Technically equipped with a mouse coloscopic, computer-aided system we are monitoring the progress of colitis and the development of tumor growth. IL-12 deficient mice develop less colitis, but are more susceptible to cancer. Additionally, in vitro we have shown that the NADPH oxidase protein p47phox down regulates IL-12 in dendritic cells. Currently we are focusing on the impact of p47phox redox and redox-independent regulation of IL-12 and IL-23 in the colitis/cancerogenesis mouse model (Cornelia Richter, Martina Herrero San Juan)
In a second project we acknowledge newly developing concepts in cancer therapy. Cytostatic agents that simultaneously exhibit immune stimulatory activity hold a great promise as a novel approach for an integrated cancer therapy. Therefore, oneproject aims to investigate phytocompounds and S1P analogs regarding their antitumor activity on melanoma cells and their immune modulating effect on primary dendritic cells and T cells. In cooperation with the TRON/Mainz we are especially interested in their influence on the regulation of anticancerogenic interleukin IL-12 and the procancerogenic cytokine IL-23 (Kathrin Pfarr).



Selected Original Publications

Giegold O, Ogrissek N, Richter C, Schröder M, Herrero San Juan M, Pfeilschifter JM, Radeke HH.
CXCL9 causes heterologous desensitization of CXCL12-mediated memory T lymphocyte activation.
J. Immunol. 190:3696-3705, 2013

Giegold O, Ogrissek N, Radeke HH.
Response to comment on „CXCL9 causes heterologous desensitization of CXCL12-mediated memory T lymphocyte activation“.
J. Immunol. 191(2) July 2013 in press

Bergis D, Kassis V, Ranglack A, Koeberle V, Piiper A, Kronenberger B, Zeuzem S, Waidmann O, Radeke HH.
High serum levels of the Interleukin receptor soluble ST2 as a negative prognostic factor in hepatocellular carcinoma.
Trans. Onc. 6(3):311-318, 2013

Schröder M, Richter C, Juan MH, Maltusch K, Giegold O, Quintini G, Pfeilschifter JM, Huwiler A, Radeke HH.
The sphingosine kinase 1 and S1P1 axis specifically counteracts LPS-induced IL-12p70 production in immune cells of the spleen.
MolImmunol. 48(9-10):1139-1148, 2011

Richter C, Juan MH, Will J, Brandes RP, Kalinke U, Akira S, Pfeilschifter JM, Hultqvist M, Holmdahl R, Radeke HH.
Ncf1 provides a reactive oxygen species-independent negative feedback regulation of TLR9-induced IL-12p70 in murine dendritic cells.
J. Immunol. 182(7):4183-4191, 2009


Supported by:

DFGfunding: SPP1267, GRK1172, and SFB1039; Merck KGaA; TRIP (Else-Kröner-Fresenius); Dr. Hans-Kröner-Foundation; Bilateral European Erasmus Program

 
 
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Sekretariat Prof. Dr. Josef Pfeilschifter

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