Ulrike Erben

The Elongated First Fibronectin Type III Domain of Collagen XIV Is an Inducer of Quiescence and Differentiation in Fibroblasts and Preadipocytes

Collagen XIV (CXIV) is a fibril-associated collagen that is mainly expressed in well differentiated tissues and in late embryonic development. Because CXIV is almost absent in proliferating and/or dedifferentiated tissues, a functional role in maintaining cell differentiation is suspected. We demonstrate antiproliferative, quiescence- and differentiation-inducing effects of human CXIV and its recombinant fragments on mesenchymal cells. In primary human fibroblasts, in mouse 3T3 fibroblasts and in 3T3-L1 preadipocytes, CXIV reduced de novo DNA synthesis by 75%, whereas cell numbers and viability remained unaltered. Cells showed no signs of apoptosis, and maximal proliferation was restored when serum was supplemented, thus indicating that CXIV induced reversible cellular quiescence. Exposure of fibroblasts to CXIV in vitro led to cellular bundles and clusters. CXIV also triggered trans-differentiation of 3T3-L1 preadipocytes into adipocytes, as could be shown by lipid accumulation and by expression of the glucose transporter Glut4. These effects were also observed with the amino-terminal recombinant fragment Gln29-Pro154 that harbors the first fibronectin type III domain and a 39-amino-acid extension, whereas no activity was found for all other recombinant CXIV fragments. Based on these finding the development of small molecular analogs that modulate fibroblast cell growth and differentiation, e.g. in wound healing and fibrosis, seems feasible.

Role of visceral fat in colonic inflammation: from Crohn's disease to diverticulitis.

Purpose of review The composition of activated adipose tissue with adipocytes secreting a broad spectrum of immune-modulatory adipokines next to adipose tissue-derived stromal cells and professional immune effector cells in the visceral fat creates a complex network of inflammatory processes shaping local immune responses in the adjacent inflamed intestinal mucosa. Recent findings In Crohns disease a particular phenomenon called ‘creeping fat’ can be observed. Here the hyperplastic mesenteric fat tissue not only grows around inflamed small intestinal segments but also furthermore affects the regulation of the mucosal immune system. Diverticular disease is highly prevalent in the western world but the knowledge about its immunopathology remains incomplete. Interestingly, adipose tissue also frequently covers the basolateral site of inflamed diverticula, hence locally reflecting the phenomenon seen in Crohns disease. Summary This review aims to summarize the current knowledge in which measures this intraabdominal fat participates in the regulation of intestinal inflammation with a particular focus on differences and possible parallels in Crohns disease and diverticulitis. The available data allow for suggesting that each inflamed diverticula mechanistically reflects Crohns disease on a miniature scale.

CS‐1, a novel c‐kithi+ acute myeloid leukemia cell line with dendritic cell differentiation capacity and absent immunogenicity

Complex cytogenetic abnormalities confer dismal prognoses in myeloid malignancies. Even bone marrow transplantation from siblings or matched unrelated donors offer minimal chances for cure, suggesting that these cases are not only refractory to chemotherapy but also resist the graft‐vs.‐leukemia effect. We herein describe the first permanent, factor‐independent c‐kithi+ cell line CS‐1 derived from an unrelated donor stem cell transplanted patient with relapsed acute myeloid leukemia (AML)‐M5a of high‐risk karyotype [monosomy 7, t(2;11)(q31;p13), t(10;12)(q24;q24)]. Having the same karyotype, CS‐1 exhibits an autonomous growth pattern and responds to stem cell factor (SCF). CS‐1 did not induce T cell activation in mixed‐lymphocyte‐tumor‐cultures (MLTCs) and, when used as third party stimulators, decreased T cell proliferation in mixed‐lymphocyte reactions (MLRs). Cytokines added exogenously or secreted from bystander T cells caused CS‐1 to differentiate into dendritic cells (DCs). CS‐1‐derived DCs, in contrast to DCs originating from non‐malignant CD34+ progenitor cells, had virtually no T cell stimulatory effect, indicating that CS‐1 is both immunosuppressive and poorly immunogenic. These properties may partially be due to the detected downregulation of costimulatory molecules and appear to involve a soluble factor. CS‐1 cells injected subcutaneously (s.c.) to non‐obese diabetes/severe combined immunodeficient (NOD/SCID) mice produced solid tumors, disseminating into bone marrow and spleen. The data show that transforming AML blasts with high‐risk karyotype into DCs is insufficient to restore their immunogenicity and that the CS‐1 cell line is useful to identify tumor‐related immunosuppressive mechanisms in vitro and in vivo.

The Role of T-Cell Subsets in Chronic Inflammation in Celiac Disease and Inflammatory Bowel Disease Patients: More Common Mechanisms or More Differences?

Background: Chronic intestinal inflammation due to noninfectious causes represents a growing health issue all over the world. Celiac disease as well as inflammatory bowel diseases (IBD) like Crohns disease and ulcerative and microscopic colitis involve uncontrolled T-cell activation and T-cell-mediated damage as common denominators. Therefore, diagnosis and treatment decisions clearly benefit from the knowledge of the intricacies of the systemic and the local T-cell activity. Summary: Depending on the cytokine milieu, CD4+ T cells can differentiate into proinflammatory T helper 1 (Th1), anti-inflammatory Th2, antimicrobial Th17, pleiotropic Th9, tissue-instructing Th22 cells, and in the regulatory compartment forkhead box protein 3+ Treg, suppressive Tr1 or Th3 cells. Additionally, follicular Th cells provide B-cell help in antibody class switching; cytotoxic CD8+ T cells target virus-infected or tumor cells. This review discusses our current knowledge on the contribution of defined T-cell subpopulations to establishing and maintaining chronic intestinal inflammation in either of the above entities. It also puts emphasis on the differences in the prevalence of these diseases between Eastern and Western countries. Key Messages: In celiac disease, the driving role of T cells in the lamina propria and in the epithelium mainly specific for two defined antigens is well established. Differences in genetics and lifestyle between Western and Eastern countries were instrumental in understanding underlying mechanisms. In IBD, the vast amount of potential antigens and the corresponding antigen-specific T cells makes it unlikely to find universal triggers. Increased mucosal CD4+ regulatory T cells in all four entities fail to control or abrogate local inflammatory processes. Thus, prevailing differences in the functional T-cell subtypes driving chronic intestinal inflammation in celiac disease and IBD at best allow some overlap in the treatment options for either disease.