-
[show abstract]
[hide abstract]
ABSTRACT: Janus kinases (Jaks) are critical signaling elements for a large subset of cytokines. As a consequence they play pivotal roles in the patho-physiology of many diseases including neoplastic and autoimmune diseases. Small molecule Jak inhibitors as therapeutic agents have become a reality and the palette of such inhibitors will likely expand. This review will summarize our current knowledge on these key enzymes and their associated pharmaceutical inhibitors.
The Open Rheumatology Journal 01/2012; 6:232-44.
-
Elaine F Remmers,
Fulya Cosan,
Yohei Kirino,
Michael J Ombrello,
Neslihan Abaci,
Colleen Satorius,
Julie M Le,
Barbara Yang,
Benjamin D Korman,
Aris Cakiris, [......],
Farida Fortune,
Marwen Ghabra,
William E R Ollier,
Young-Hun Cho,
Dongsik Bang, John O'Shea,
Graham R Wallace,
Massimo Gadina,
Daniel L Kastner,
Ahmet Gül
[show abstract]
[hide abstract]
ABSTRACT: Behçet's disease is a genetically complex disease of unknown etiology characterized by recurrent inflammatory attacks affecting the orogenital mucosa, eyes and skin. We performed a genome-wide association study with 311,459 SNPs in 1,215 individuals with Behçet's disease (cases) and 1,278 healthy controls from Turkey. We confirmed the known association of Behçet's disease with HLA-B*51 and identified a second, independent association within the MHC Class I region. We also identified an association at IL10 (rs1518111, P = 1.88 x 10(-8)). Using a meta-analysis with an additional five cohorts from Turkey, the Middle East, Europe and Asia, comprising a total of 2,430 cases and 2,660 controls, we identified associations at IL10 (rs1518111, P = 3.54 x 10(-18), odds ratio = 1.45, 95% CI 1.34-1.58) and the IL23R-IL12RB2 locus (rs924080, P = 6.69 x 10(-9), OR = 1.28, 95% CI 1.18-1.39). The disease-associated IL10 variant (the rs1518111 A allele) was associated with diminished mRNA expression and low protein production.
Nature Genetics 08/2010; 42(8):698-702. · 35.53 Impact Factor
-
Stefan Kuchen,
Wolfgang Resch,
Arito Yamane,
Nan Kuo,
Zhiyu Li,
Tirtha Chakraborty,
Lai Wei,
Arian Laurence,
Tomoharu Yasuda,
Siying Peng, [......],
Wendy Dubois,
Yoshiaki Kitamura,
Nicolas Charles,
Hong-wei Sun,
Stefan Muljo,
Pamela L Schwartzberg,
William E Paul, John O'Shea,
Klaus Rajewsky,
Rafael Casellas
[show abstract]
[hide abstract]
ABSTRACT: Although the cellular concentration of miRNAs is critical to their function, how miRNA expression and abundance are regulated during ontogeny is unclear. We applied miRNA-, mRNA-, and ChIP-Seq to characterize the microRNome during lymphopoiesis within the context of the transcriptome and epigenome. We show that lymphocyte-specific miRNAs are either tightly controlled by polycomb group-mediated H3K27me3 or maintained in a semi-activated epigenetic state prior to full expression. Because of miRNA biogenesis, the cellular concentration of mature miRNAs does not typically reflect transcriptional changes. However, we uncover a subset of miRNAs for which abundance is dictated by miRNA gene expression. We confirm that concentration of 5p and 3p miRNA strands depends largely on free energy properties of miRNA duplexes. Unexpectedly, we also find that miRNA strand accumulation can be developmentally regulated. Our data provide a comprehensive map of immunity's microRNome and reveal the underlying epigenetic and transcriptional forces that shape miRNA homeostasis.
Immunity 06/2010; 32(6):828-39. · 21.64 Impact Factor
-
Wendy T Watford,
Chun-Chi Wang,
Christos Tsatsanis,
Lisa A Mielke,
Aristides G Eliopoulos,
Constantine Daskalakis,
Nicolas Charles,
Sandra Odom,
Juan Rivera, John O'Shea,
Philip N Tsichlis
[show abstract]
[hide abstract]
ABSTRACT: The protein kinase encoded by the Tpl2 proto-oncogene regulates ERK activation and cytokine gene expression in macrophages in response to LPS and TNF-alpha. In this study we show that OVA-immunized Tpl2(-/-) mice express high levels of IgE and develop more severe bronchoalveolar eosinophilic inflammation than Tpl2(+/+) controls, when challenged with OVA intranasally. Bronchoalveolar exudates and supernatants of OVA-stimulated splenocytes from immunized Tpl2(-/-) mice express elevated levels of IL-4 and IL-5, suggesting that Tpl2 ablation promotes the Th2 polarization of the T cell response. Anti-CD3 stimulation of CD4(+) T cells of wild-type and Tpl2 knockout mice revealed that Tpl2 ablation gives rise to a cell autonomous T cell defect that is primarily responsible for the Th2 polarization of the T cell response to Ag. This observation was further supported by experiments addressing the expression of Th1 and Th2 cytokines in OVA-stimulated mixed cultures of CD4(+) T cells from Tpl2(+/+)/OT2 or Tpl2(-/-)/OT2 mice and dendritic cells from Tpl2(+/+) or Tpl2(-/-) mice. Further studies revealed that Th1 cells express significantly higher levels of Tpl2 than Th2 cells. As a result, Tpl2(-/-) Th1 cells exhibit a stronger defect in ERK activation by anti-CD3 than Th2 cells and express low levels of T-bet. Given that the development of Th1 and Th2 cells depends on positive feedback signals from the T cells, themselves, the functional defect of the Tpl2(-/-) Th1 cells provides a mechanistic explanation for the T cell autonomous Th2 polarization in Tpl2(-/-) mice.
The Journal of Immunology 12/2009; 184(1):105-13. · 5.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Recently, new complexities in cell fate decision for helper T cells have emerged. One new lineage, which has come to be called Th17 cells, selectively produces proinflammatory cytokines including interleukin-17 (IL-17, A and F), IL-21, and IL-22. In conjunction with transforming growth factor beta-1 (TGFbeta-1), IL-6, IL-21, and IL-23, which activate the transcription factor, signal transducer, and activator of transcription 3 (Stat3), the expression of another transcription factor, retinoic acid-related orphan receptor-gammat (RORgammat) leads to the differentiation of Th17 cells in mice. Other cytokines including IL-2, IL-4, interferon-gamma (IFN-gamma), and IL-27 inhibit Th17 differentiation. However, IL-2 acting with TGFbeta-1 induces differentiation of naïve CD4+ T cells to become regulatory T cells (Tregs). Th17 cells are now known to play an important role not only in the pathogenesis of inflammation and autoimmune diseases, but also host defense against extracellular bacteria. Conversely, extensive data substantiate the role of Tregs as essential in maintenance of peripheral tolerance. Selectively targeting Tregs and Th17 cells are likely to be important strategies in the treatment of inflammatory and autoimmune diseases in humans.
Modern Rheumatology 09/2008; 18(6):533-41. · 1.58 Impact Factor
-
Joshua D Milner,
Jason M Brenchley,
Arian Laurence,
Alexandra F Freeman,
Brenna J Hill,
Kevin M Elias,
Yuka Kanno,
Christine Spalding,
Houda Z Elloumi,
Michelle L Paulson,
Joie Davis,
Amy Hsu,
Ava I Asher, John O'Shea,
Steven M Holland,
William E Paul,
Daniel C Douek
[show abstract]
[hide abstract]
ABSTRACT: The autosomal dominant hyper-IgE syndrome (HIES, 'Job's syndrome') is characterized by recurrent and often severe pulmonary infections, pneumatoceles, eczema, staphylococcal abscesses, mucocutaneous candidiasis, and abnormalities of bone and connective tissue. Mutations presumed to underlie HIES have recently been identified in stat3, the gene encoding STAT3 (signal transducer and activator of transcription 3) (refs 3, 4). Although impaired production of interferon-gamma and tumour-necrosis factor by T cells, diminished memory T-cell populations, decreased delayed-type-hypersensitivity responses and decreased in vitro lymphoproliferation in response to specific antigens have variably been described, specific immunological abnormalities that can explain the unique susceptibility to particular infections seen in HIES have not yet been defined. Here we show that interleukin (IL)-17 production by T cells is absent in HIES individuals. We observed that ex vivo T cells from subjects with HIES failed to produce IL-17, but not IL-2, tumour-necrosis factor or interferon-gamma, on mitogenic stimulation with staphylococcal enterotoxin B or on antigenic stimulation with Candida albicans or streptokinase. Purified naive T cells were unable to differentiate into IL-17-producing (T(H)17) T helper cells in vitro and had lower expression of retinoid-related orphan receptor (ROR)-gammat, which is consistent with a crucial role for STAT3 signalling in the generation of T(H)17 cells. T(H)17 cells have emerged as an important subset of helper T cells that are believed to be critical in the clearance of fungal and extracellular bacterial infections. Thus, our data suggest that the inability to produce T(H)17 cells is a mechanism underlying the susceptibility to the recurrent infections commonly seen in HIES.
Nature 05/2008; 452(7188):773-6. · 36.28 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Classically naïve CD4(+) have been thought to differentiate into two possible lineages, T helper 1 (Th1) or T helper 2 (Th2) cells. Within this paradigm the pathogenesis of autoimmunity was suggested to predominantly relate to Th1 cells and the production of IFN-gamma. However, there were many aspects of this model that did not seem to fit, not the least of which was that IFN-gamma was protective in some models of autoimmunity. During the past 2 years, remarkable progress has been made to characterize a new lineage of helper T cells. Designated Th17 cells, this lineage selectively produces proinflammatory cytokines including IL-17, IL-21, and IL-22. In the mouse, the differentiation of this new lineage is initiated by TGFbeta-1 and IL-6 and IL-21, which activate Stat3 and induce the expression of the transcription factor retinoic acid-related orphan receptor (RORgammat). IL-23, which also activates Stat3, apparently serves to maintain Th17 cells in vivo. In human cells, IL-1, IL-6, and IL-23 promote human Th17 differentiation, but TGFbeta-1 is reportedly not needed. Emerging data have suggested that Th17 plays an essential role in the host defense against extracellular bacteria and fungi and in pathogenesis of autoimmune diseases. Selectively targeting the Th17 lineage may be beneficial for the treatment of inflammatory and autoimmune diseases.
Immunologic Research 02/2008; 41(2):87-102. · 3.03 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Ewing sarcoma gene EWS encodes a putative RNA-binding protein with proposed roles in transcription and splicing, but its physiological role in vivo remains undefined. Here, we have generated Ews-deficient mice and demonstrated that EWS is required for the completion of B cell development and meiosis. Analysis of Ews(-/-) lymphocytes revealed a cell-autonomous defect in precursor B lymphocyte (pre-B lymphocyte) development. During meiosis, Ews-null spermatocytes were deficient in XY bivalent formation and showed reduced meiotic recombination, resulting in massive apoptosis and complete arrest in gamete maturation. Inactivation of Ews in mouse embryonic fibroblasts resulted in premature cellular senescence, and the mutant animals showed hypersensitivity to ionizing radiation. Finally, we showed that EWS interacts with lamin A/C and that loss of EWS results in a reduced lamin A/C expression. Our findings reveal essential functions for EWS in pre-B cell development and meiosis, with proposed roles in DNA pairing and recombination/repair mechanisms. Furthermore, we demonstrate a novel role of EWS in cellular senescence, possibly through its interaction and modulation of lamin A/C.
Journal of Clinical Investigation 06/2007; 117(5):1314-23. · 15.39 Impact Factor
-
Molecular Interventions 09/2005; 5(4):211-5. · 4.59 Impact Factor
-
Zhengqi Wu,
Margaret Roberts,
Melissa Porter,
Fabianne Walker,
E John Wherry,
John Kelly,
Massimo Gadina,
Elisabeth M Silva,
George A DosReis,
Marcela F Lopes, John O'Shea,
Warren J Leonard,
Rafi Ahmed,
Richard M Siegel
[show abstract]
[hide abstract]
ABSTRACT: Viral FLIPs (vFLIPs) interfere with apoptosis signaling by death-domain-containing receptors in the TNFR superfamily (death receptors). In this study, we show that T cell-specific transgenic expression of MC159-vFLIP from the human Molluscum contagiosum virus blocks CD95-induced apoptosis in thymocytes and peripheral T cells, but also impairs postactivation survival of in vitro activated primary T cells despite normal early activation parameters. MC159 vFLIP impairs T cell development to a lesser extent than does Fas-associated death domain protein deficiency or another viral FLIP, E8. In the periphery, vFLIP expression leads to a specific deficit of functional memory CD8(+) T cells. After immunization with a protein Ag, Ag-specific CD8(+) T cells initially proliferate, but quickly disappear and fail to produce Ag-specific memory CD8(+) T cells. Viral FLIP transgenic mice exhibit impaired CD8(+) T cell responses to lymphocytic choriomeningitis virus and Trypanosoma cruzi infections, and a specific defect in CD8(+) T cell recall responses to influenza virus was seen. These results suggest that vFLIP expression in T cells blocks signals necessary for the sustained survival of CD8(+) T cells and the generation of CD8(+) T cell memory. Through this mechanism, vFLIP proteins expressed by T cell tropic viruses may impair the CD8(+) T cell immune responses directed against them.
The Journal of Immunology 06/2004; 172(10):6313-23. · 5.79 Impact Factor
-
Journal of Clinical Investigation 06/2002; 109(10):1261-9. · 15.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The biological activities of IL-12 are mediated through a specific, high-affinity receptor composed of IL-12 receptor(R)β1 and IL-12Rβ2 subunits that exist primarily on T and NK cells. Remarkably, the expression of IL-12Rβ2 on CD4+ T cells in mouse and humans appears to be differentially regulated by IFN- and IFN- , respectively. Using an antibody specific for the human IL-12Rβ2 subunit, the effect of IFN- , IFN- , IL-12 and IL-2 on the regulation of IL-12R expression and IL-12 responsiveness of human T and NK cells was assessed. The presence of IFN- or IFN- in cultures enhanced IL-12Rβ2 expression of CD4+ and CD8+ T cells. The enhancing effect of IFN- and IFN- was independent of endogenous IL-12. Furthermore, the clearest effects of IFN- and IFN- on IL-12Rβ2 expression on T cells were seen by abrograting the inhibition induced by the presence of IL-4 in cultures. In contrast to T cells, IFN- and IFN- had little effect on regulating IL-12Rβ2 expression on human NK cells. Taken together, these data show that there is differential regulation of IL-12Rβ2 expression by IFN- and IFN- on human T and NK cells.
European Journal of Immunology 05/2000; 30(5):1364 - 1374. · 5.10 Impact Factor
