TY  - JOUR
A1  - Alrefai, Hani
A1  - Muhammad, Khalid
A1  - Rudolf, Ronald
A1  - Pham, Duong Anh Thuy
A1  - Klein-Hessling, Stefan
A1  - Patra, Amiya K.
A1  - Avots, Andris
A1  - Bukur, Valesca
A1  - Sahin,, Ugur
A1  - Tenzer, Stefan
A1  - Goebeler, Matthias
A1  - Kerstan, Andreas
A1  - Serfling, Edgar
T1  - NFATc1 supports imiquimod-induced skin inflammation by suppressing IL-10 synthesis in B cells
JF  - Nature Communications
N2  - Epicutaneous application of Aldara cream containing the TLR7 agonist imiquimod (IMQ) to mice induces skin inflammation that exhibits many aspects of psoriasis, an inflammatory human skin disease. Here we show that mice depleted of B cells or bearing interleukin (IL)-10-deficient B cells show a fulminant inflammation upon IMQ exposure, whereas ablation of NFATc1 in B cells results in a suppression of Aldara-induced inflammation. In vitro, IMQ induces the proliferation and IL-10 expression by B cells that is blocked by BCR signals inducing NFATc1. By binding to HDAC1, a transcriptional repressor, and to an intronic site of the Il10 gene, NFATc1 suppresses IL-10 expression that dampens the production of tumour necrosis factor-α and IL-17 by T cells. These data indicate a close link between NFATc1 and IL-10 expression in B cells and suggest NFATc1 and, in particular, its inducible short isoform, NFATc1/αA, as a potential target to treat human psoriasis.
KW  - B cells
KW  - psoriasis
KW  - interleukins
KW  - inflammation
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173053
VL  - 7
ER  - 
TY  - JOUR
A1  - Giampaolo, Sabrina
A1  - Wójcik, Gabriela
A1  - Serfling, Edgar
A1  - Patra, Amiya K.
T1  - Interleukin-2-regulatory T cell axis critically regulates maintenance of hematopoietic stem cells
JF  - Oncotarget
N2  - The role of IL-2 in HSC maintenance is unknown. Here we show that Il2\(^{−/-}\) mice develop severe anomalies in HSC maintenance leading to defective hematopoiesis. Whereas, lack of IL-2 signaling was detrimental for lympho- and erythropoiesis, myelopoiesis was enhanced in Il2\(^{−/-}\) mice. Investigation of the underlying mechanisms of dysregulated hematopoiesis in Il2\(^{−/-}\) mice shows that the IL-2-T\(_{reg}\) cell axis is indispensable for HSC maintenance and normal hematopoiesis. Lack of T\(_{reg}\) activity resulted in increased IFN-γ production by activated T cells and an expansion of the HSCs in the bone marrow (BM). Though, restoring T\(_{reg}\) population successfully rescued HSC maintenance in Il2\(^{-/-}\) mice, preventing IFN-γ activity could do the same even in the absence of T\(_{reg}\) cells. Our study suggests that equilibrium in IL-2 and IFN-γ activity is critical for steady state hematopoiesis, and in clinical conditions of BM failure, IL-2 or anti-IFN-γ treatment might help to restore hematopoiesis.
KW  - immunity
KW  - hematopoietic stem cells
KW  - IL-2
KW  - treg cells
KW  - IL-10
KW  - IFN-γ
KW  - immunology and microbiology section
KW  - immune response
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170947
VL  - 8
IS  - 18
ER  - 
TY  - JOUR
A1  - Serfling, Edgar
A1  - Rudolf, Ronald
A1  - Busch, Rhoda
A1  - Patra, Amiya K.
A1  - Muhammad, Khalid
A1  - Avots, Andris
A1  - Andrau, Jean-Christophe
A1  - Klein-Hessling, Stefan
T1  - Architecture and expression of the Nfatc1 gene in lymphocytes
N2  - In lymphocytes, the three NFAT factors NFATc1 (also designated as NFAT2), NFATc2 (NFAT1), and NFATc3 (NFAT4 or NFATx) are expressed and are the targets of immune receptor signals, which lead to a rapid rise of intracellular Ca++, the activation of phosphatase calcineurin, and to the activation of cytosolic NFATc proteins. In addition to rapid activation of NFAT factors, immune receptor signals lead to accumulation of the short NFATc1/αA isoform in lymphocytes which controls their proliferation and survival. In this mini-review, we summarize our current knowledge on the structure and transcription of the Nfatc1 gene in lymphocytes, which is controlled by two promoters, two poly A addition sites and a remote downstream enhancer. The Nfatc1 gene resembles numerous primary response genes (PRGs) induced by LPS in macrophages. Similar to the PRG promoters, the Nfatc1 promoter region is organized in CpG islands, forms DNase I hypersensitive sites, and is marked by histone tail modifications before induction. By studying gene induction in lymphocytes in detail, it will be important to elucidate whether the properties of the Nfatc1 induction are not only typical for the Nfatc1 gene but also for other transcription factor genes expressed in lymphocytes.
KW  - transcription
KW  - chromatin
KW  - induction
KW  - lymphocytes
KW  - Nfatc1
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-112718
ER  -