Wilting, Jörg

[["dc.bibliographiccitation.firstpage","1"],["dc.bibliographiccitation.journal","Journal of Cellular and Molecular Medicine"],["dc.bibliographiccitation.lastpage","9"],["dc.contributor.author","Malik, Gesa"],["dc.contributor.author","Wilting, Jörg"],["dc.contributor.author","Hess, Clemens Friedrich"],["dc.contributor.author","Ramadori, Giuliano"],["dc.contributor.author","Malik, Ihtzaz Ahmed"],["dc.date.accessioned","2019-07-09T11:50:04Z"],["dc.date.available","2019-07-09T11:50:04Z"],["dc.date.issued","2019"],["dc.description.abstract","The mechanisms of radiation-induced liver damage are poorly understood. We investigated if tumour necrosis factor (TNF)-α acts synergistically with irradiation, and how its activity is influenced by platelet endothelial cell adhesion molecule-1 (PECAM-1). We studied murine models of selective single-dose (25 Gy) liver irradiation with and without TNF-α application (2 μg/mouse; i.p.). In serum of wild-type (wt)-mice, irradiation induced a mild increase in hepatic damage marker aspartate aminotransferase (AST) in comparison to sham-irradiated controls. AST levels further increased in mice treated with both irradiation and TNF-α. Accordingly, elevated numbers of leucocytes and increased expression of the macrophage marker CD68 were observed in the liver of these mice. In parallel to hepatic damage, a consecutive decrease in expression of hepatic PECAM-1 was found in mice that received radiation or TNF-α treatment alone. The combination of radiation and TNF-α induced an additional significant decline of PECAM-1. Furthermore, increased expression of hepatic lipocalin-2 (LCN-2), a hepatoprotective protein, was detected at mRNA and protein levels after irradiation or TNF-α treatment alone and the combination of both. Signal transducer and activator of transcription-3 (STAT-3) seems to be involved in the signalling cascade. To study the involvement of PECAM-1 in hepatic damage more deeply, the liver of both wt- and PECAM-1-knock-out-mice were selectively irradiated (25 Gy). Thereby, ko-mice showed higher liver damage as revealed by elevated AST levels, but also increased hepatoprotective LCN-2 expression. Our studies show that TNF-α has a pivotal role in radiation-induced hepatic damage. It acts in concert with irradiation and its activity is modulated by PECAM-1, which mediates pro- and anti-inflammatory signalling."],["dc.identifier.doi","10.1111/jcmm.14224"],["dc.identifier.pmid","30761739"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15851"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59695"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","1582-4934"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","PECAM-1 modulates liver damage induced by synergistic effects of TNF-α and irradiation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1"],["dc.bibliographiccitation.issue","105"],["dc.bibliographiccitation.journal","BMC cancer"],["dc.bibliographiccitation.lastpage","17"],["dc.bibliographiccitation.volume","7"],["dc.contributor.author","Norgall, Susanne"],["dc.contributor.author","Papoutsi, Maria"],["dc.contributor.author","Rössler, Jochen"],["dc.contributor.author","Schweigerer, Lothar"],["dc.contributor.author","Wilting, Jörg"],["dc.contributor.author","Weich, Herbert A."],["dc.date.accessioned","2019-07-10T08:13:00Z"],["dc.date.available","2019-07-10T08:13:00Z"],["dc.date.issued","2007"],["dc.description.abstract","Background: Lymphangiomas are neoplasias of childhood. Their etiology is unknown and a causal therapy does not exist. The recent discovery of highly specific markers for lymphatic endothelial cells (LECs) has permitted their isolation and characterization, but expression levels and stability of molecular markers on LECs from healthy and lymphangioma tissues have not been studied yet. We addressed this problem by profiling LECs from normal dermis and two children suffering from lymphangioma, and also compared them with blood endothelial cells (BECs) from umbilical vein, aorta and myometrial microvessels. Methods: Lymphangioma tissue samples were obtained from two young patients suffering from lymphangioma in the axillary and upper arm region. Initially isolated with anti-CD31 (PECAM-1) antibodies, the cells were separated by FACS sorting and magnetic beads using anti-podoplanin and/or LYVE-1 antibodies. Characterization was performed by FACS analysis, immunofluorescence staining, ELISA and micro-array gene analysis. Results: LECs from foreskin and lymphangioma had an almost identical pattern of lymphendothelial markers such as podoplanin, Prox1, reelin, cMaf and integrin-a1 and -a9. However, LYVE-1 was down-regulated and VEGFR-2 and R-3 were up-regulated in lymphangiomas. Prox1 was constantly expressed in LECs but not in any of the BECs. Conclusion: LECs from different sources express slightly variable molecular markers, but can always be distinguished from BECs by their Prox1 expression. High levels of VEGFR-3 and -2 seem to contribute to the etiology of lymphangiomas."],["dc.identifier.fs","171198"],["dc.identifier.ppn","560267541"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/4366"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/61096"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.orgunit","Universitätsmedizin Göttingen"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.subject.ddc","610"],["dc.title","Elevated expression of VEGFR-3 in lymphatic endothelial cells from lymphangiomas"],["dc.title.alternative","Research article"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","7347"],["dc.bibliographiccitation.issue","41"],["dc.bibliographiccitation.journal","World Journal of Gastroenterology"],["dc.bibliographiccitation.lastpage","7358"],["dc.bibliographiccitation.volume","23"],["dc.contributor.author","Malik, Ihtzaz Ahmed"],["dc.contributor.author","Wilting, Jörg"],["dc.contributor.author","Ramadori, Giuliano"],["dc.contributor.author","Naz, Naila"],["dc.date.accessioned","2019-07-09T11:44:36Z"],["dc.date.available","2019-07-09T11:44:36Z"],["dc.date.issued","2017"],["dc.description.abstract","AIM To studied iron metabolism in liver, spleen, and serum after acute liver-damage, in relation to surrogate markers for liver-damage and repair. METHODS Rats received intraperitoneal injection of the hepatotoxin thioacetamide (TAA), and were sacrificed regularly between 1 and 96 h thereafter. Serum levels of transaminases and iron were measured using conventional laboratory assays. Liver tissue was used for conventional histology, immunohistology, and iron staining. The expression of acute-phase cytokines, ferritin light chain (FTL), and ferritin heavy chain (FTH) was investigated in the liver by qRT-PCR. Western blotting was used to investigate FTL and FTH in liver tissue and serum. Liver and spleen tissue was also used to determine iron concentrations. RESULTS After a short initial decrease, iron serum concentrations increased in parallel with serum transaminase (aspartate aminotransferase and alanine aminotransferase) levels, which reached a maximum at 48 h, and decreased thereafter. Similarly, after 48 h a significant increase in FTL, and after 72h in FTH was detected in serum. While earliest morphological signs of inflammation in liver were visible after 6 h, increased expression of the two acute-phase cytokines IFN-γ (1h) and IL-1β (3h) was detectable earlier, with maximum values after 12-24 h. Iron concentrations in liver tissue increased steadily between 1 h and 48 h, and remained high at 96 h. In contrast, spleen iron concentrations remained unchanged until 48 h, and increased mildly thereafter (96 h). Although tissue iron staining was negative, hepatic FTL and FTH protein levels were strongly elevated. Our results reveal effects on hepatic iron concentrations after direct liver injury by TAA. The increase of liver iron concentrations may be due to the uptake of a significant proportion of the metal by healthy hepatocytes, and only to a minor extent by macrophages, as spleen iron concentrations do not increase in parallel. The temporary increase of iron, FTH and transaminases in serum is obviously due to their release by damaged hepatocytes. CONCLUSION Increased liver iron levels may be the consequence of hepatocyte damage. Iron released into serum by damaged hepatocytes is obviously transported back and stored via ferritins."],["dc.identifier.doi","10.3748/wjg.v23.i41.7347"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14835"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59046"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","2219-2840"],["dc.rights","CC BY-NC 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc/4.0"],["dc.subject.ddc","610"],["dc.title","Reabsorption of iron into acutely damaged rat liver: A role for ferritins"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e0200343"],["dc.bibliographiccitation.issue","7"],["dc.bibliographiccitation.journal","PLOS ONE"],["dc.bibliographiccitation.volume","13"],["dc.contributor.author","Blesinger, Hannah"],["dc.contributor.author","Kaulfuß, Silke"],["dc.contributor.author","Aung, Thiha"],["dc.contributor.author","Schwoch, Sonja"],["dc.contributor.author","Prantl, Lukas"],["dc.contributor.author","Rößler, Jochen"],["dc.contributor.author","Wilting, Jörg"],["dc.contributor.author","Becker, Jürgen"],["dc.date.accessioned","2019-07-09T11:45:49Z"],["dc.date.available","2019-07-09T11:45:49Z"],["dc.date.issued","2018"],["dc.description.abstract","Lymphatic malformations (LM) are characterized by the overgrowth of lymphatic vessels during pre- and postnatal development. Macrocystic, microcystic and combined forms of LM are known. The cysts are lined by lymphatic endothelial cells (LECs). Resection and sclerotherapy are the most common treatment methods. Recent studies performed on LM specimens in the United States of America have identified activating mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene in LM. However, whole tissue but not isolated cell types were studied. Here, we studied LM tissues resected at the University Hospitals Freiburg and Regensburg, Germany. We isolated LECs and fibroblasts separately, and sequenced the commonly affected exons 8, 10, and 21 of the PIK3CA gene. We confirm typical monoallelic mutations in 4 out of 6 LM-derived LEC lines, and describe two new mutations i.) in exon 10 (c.1636C>A; p.Gln546Lys), and ii.) a 3bp in-frame deletion of GAA (Glu109del). LM-derived fibroblasts did not possess such mutations, showing cell-type specificity of the gene defect. High activity of the PIK3CA-AKT- mTOR pathway was demonstrated by hyperphosphorylation of AKT-Ser473 in all LM-derived LECs (including the ones with newly identified mutations), as compared to normal LECs. Additionally, hyperphosphorylation of ERK was seen in all LM-derived LECs, except for the one with Glu109del. In vitro, the small molecule kinase inhibitors Buparlisib/BKM-120, Wortmannin, and Ly294002, (all inhibitors of PIK3CA), CAL-101 (inhibitor of PIK3CD), MK-2206 (AKT inhibitor), Sorafenib (multiple kinases inhibitor), and rapamycin (mTOR inhibitor) significantly blocked proliferation of LM-derived LECs in a concentration-dependent manner, but also blocked proliferation of normal LECs. However, MK-2206 appeared to be more specific for mutated LECs, except in case of Glu109 deletion. In sum, children that are, or will be, treated with kinase inhibitors must be monitored closely."],["dc.identifier.doi","10.1371/journal.pone.0200343"],["dc.identifier.pmid","29985963"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15320"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59313"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","1932-6203"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.subject.ddc","610"],["dc.title","PIK3CA mutations are specifically localized to lymphatic endothelial cells of lymphatic malformations"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","5"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","BMC Immunology"],["dc.bibliographiccitation.volume","19"],["dc.contributor.author","Lohrberg, Melanie"],["dc.contributor.author","Pabst, Reinhard"],["dc.contributor.author","Wilting, Jörg"],["dc.date.accessioned","2019-07-09T11:45:11Z"],["dc.date.available","2019-07-09T11:45:11Z"],["dc.date.issued","2018"],["dc.description.abstract","BACKGROUND: The lymphatic vascular pattern in the head of mice has rarely been studied, due to problems of sectioning and immunostaining of complex bony structures. Therefore, the association of head lymphoid tissues with the lymphatics has remained unknown although the mouse is the most often used species in immunology. RESULTS: Here, we studied the association of nasal and nasolacrimal duct lymphatics with lymphoid aggregates in 14-day-old and 2-month-old mice. We performed paraffin sectioning of whole, decalcified heads, and immunostaining with the lymphatic endothelial cell-specific antibodies Lyve-1 and Podoplanin. Most parts of the nasal mucous membrane do not contain any lymphatics. Only the region of the inferior turbinates contains lymphatic networks, which are connected to those of the palatine. Nose-associated lymphoid tissue (NALT) is restricted to the basal parts of the nose, which contain lymphatics. NALT is continued occipitally and can be found at both sides along the sphenoidal sinus, again in close association with lymphatic networks. Nasal lymphatics are connected to those of the ocular region via a lymphatic network along the nasolacrimal duct (NLD). By this means, lacrimal duct-associated lymphoid tissue (LDALT) has a dense supply with lymphatics. CONCLUSIONS: NALT and LDALT play a key role in the immune system of the mouse head, where they function as primary recognition sites for antigens. Using the dense lymphatic networks along the NLD described in this study, these antigens reach lymphatics near the palatine and are further drained to lymph nodes of the head and neck region. NALT and LDALT develop in immediate vicinity of lymphatic vessels. Therefore, we suggest a causative connection of lymphatic vessels and the development of lymphoid tissues."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2018"],["dc.identifier.doi","10.1186/s12865-018-0242-3"],["dc.identifier.pmid","29368640"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15052"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59176"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.notes.intern","In goescholar not merged with http://resolver.sub.uni-goettingen.de/purl?gs-1/15133 but duplicate"],["dc.relation.issn","1471-2172"],["dc.rights","CC BY 4.0"],["dc.rights.access","openAccess"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","Co-localization of lymphoid aggregates and lymphatic networks in nose- (NALT) and lacrimal duct-associated lymphoid tissue (LDALT) of mice."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","4739"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Scientific Reports"],["dc.bibliographiccitation.volume","9"],["dc.contributor.author","Lutze, Grit"],["dc.contributor.author","Haarmann, Anna"],["dc.contributor.author","Demanou Toukam, Jules A"],["dc.contributor.author","Buttler, Kerstin"],["dc.contributor.author","Wilting, Jörg"],["dc.contributor.author","Becker, Jürgen"],["dc.date.accessioned","2019-07-09T11:50:33Z"],["dc.date.available","2019-07-09T11:50:33Z"],["dc.date.issued","2019"],["dc.description.abstract","Development of lymphatics takes place during embryogenesis, wound healing, inflammation, and cancer. We previously showed that Wnt5a is an essential regulator of lymphatic development in the dermis of mice, however, the mechanisms of action remained unclear. Here, whole-mount immunostaining shows that embryonic day (ED) 18.5 Wnt5a-null mice possess non-functional, cyst-like and often blood-filled lymphatics, in contrast to slender, interconnected lymphatic networks of Wnt5a+/- and wild-type (wt) mice. We then compared lymphatic endothelial cell (LEC) proliferation during ED 12.5, 14.5, 16.5 and 18.5 between Wnt5a-/-, Wnt5a+/- and wt-mice. We did not observe any differences, clearly showing that Wnt5a acts independently of proliferation. Transmission electron microscopy revealed multiple defects of LECs in Wnt5a-null mice, such as malformed inter-endothelial junctions, ruffled cell membrane, intra-luminal bulging of nuclei and cytoplasmic processes. Application of WNT5A protein to ex vivo cultures of dorsal thoracic dermis from ED 15.5 Wnt5a-null mice induced flow-independent development of slender, elongated lymphatic networks after 2 days, in contrast to controls showing an immature lymphatic plexus. Reversely, the application of the WNT-secretion inhibitor LGK974 on ED 15.5 wt-mouse dermis significantly prevented lymphatic network elongation. Correspondingly, tube formation assays with human dermal LECs in vitro revealed increased tube length after WNT5A application. To study the intracellular signaling of WNT5A we used LEC scratch assays. Thereby, inhibition of autocrine WNTs suppressed horizontal migration, whereas application of WNT5A to inhibitor-treated LECs promoted migration. Inhibition of the RHO-GTPase RAC, or the c-Jun N-terminal kinase JNK significantly reduced migration, whereas inhibitors of the protein kinase ROCK did not. WNT5A induced transient phosphorylation of JNK in LECs, which could be inhibited by RAC- and JNK-inhibitors. Our data show that WNT5A induces formation of elongated lymphatic networks through proliferation-independent WNT-signaling via RAC and JNK. Non-canonical WNT-signaling is a major mechanism of extension lymphangiogenesis, and also controls differentiation of lymphatics."],["dc.identifier.doi","10.1038/s41598-019-41299-7"],["dc.identifier.pmid","30894622"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15960"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59793"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","2045-2322"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","Non-canonical WNT-signaling controls differentiation of lymphatics and extension lymphangiogenesis via RAC and JNK signaling"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]