A5017454682- Cytokine Signaling Pathways and Interactions
- T-cell and B-cell Immunology
- Immunodeficiency and Autoimmune Disorders
- Immune Cell Function and Interaction
- Psoriasis: Treatment and Pathogenesis
- Heat shock proteins research
- Immune Response and Inflammation
- Hematopoietic Stem Cell Transplantation
- Immunotherapy and Immune Responses
- Liver physiology and pathology
- Exercise and Physiological Responses
- NF-κB Signaling Pathways
- Phagocytosis and Immune Regulation
- Fibroblast Growth Factor Research
- Spaceflight effects on biology
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Acute Myeloid Leukemia Research
- Hepatitis B Virus Studies
- Liver Disease Diagnosis and Treatment
- interferon and immune responses
- Amyotrophic Lateral Sclerosis Research
- Signaling Pathways in Disease
- Steroid Chemistry and Biochemistry
- Protein Kinase Regulation and GTPase Signaling
- Whipple's Disease and Interleukins
Center for Translational Molecular Medicine
2022
Eon Corporation (United States)
2017-2021
New York University
2009-2020
Wolfram Research (United States)
2013-2016
Weizmann Institute of Science
2003-2007
The growth factor progranulin (PGRN) has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation, but its receptors remain unidentified. We report that PGRN bound directly to tumor necrosis (TNFRs) disturbed the TNFα-TNFR interaction. PGRN-deficient mice were susceptible collagen-induced arthritis, administration of reversed inflammatory arthritis. Atsttrin, an engineered protein composed three fragments, exhibited selective TNFR binding. Atsttrin prevented...
CD4+CD25+ Tregs regulate immunity, but little is known about their own regulation. We now report that the human 60-kDa heat shock protein (HSP60) acts as a costimulator of Tregs, both CD4+CD25int and CD4+CD25hi. Treatment with HSP60, or its peptide p277, before anti-CD3 activation significantly enhanced ability relatively low concentrations to downregulate CD4+CD25– CD8+ target T cells, detected inhibition cell proliferation IFN-γ TNF-α secretion. The enhancing effects HSP60 costimulation on...
T cell receptor (TCR)-dependent regulatory (Treg) activity controls effector (Teff) function and is inhibited by the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). Protein kinase C-theta (PKC-theta) recruitment to immunological synapse required for full Teff activation. In contrast, PKC-theta was sequestered away from Treg synapse. Furthermore, blockade enhanced function, demonstrating inhibits Treg-mediated suppression. Inhibition of protected inactivation TNF-alpha,...
Rho-associated kinase 2 (ROCK2) regulates the secretion of proinflammatory cytokines and development autoimmunity in mice. Data from a phase 1 clinical trial demonstrate that oral administration KD025, selective ROCK2 inhibitor, to healthy human subjects down-regulates ability T cells secrete IL-21 IL-17 by 90% 60%, respectively, but not IFN-γ response T-cell receptor stimulation vitro. Pharmacological inhibition with KD025 or siRNA-mediated ROCK2, ROCK1, significantly diminished STAT3...
The rho-associated coiled-coil-containing protein kinase-2 (ROCK2) signaling pathway regulates the Th17/regulatory T cells balance and controls profibrotic pathways. Selective ROCK2 inhibition with belumosudil (KD025) may offer a novel approach to management of chronic graft-versus-host disease (cGVHD).
Abstract We recently reported that soluble 60-kDa heat shock protein (HSP60) can directly activate T cells via TLR2 signaling to enhance their Th2 response. In this study we investigated whether HSP60 might also B by an innate pathway. found human (but not the Escherichia coli GroEL or Mycobacterial HSP65 molecules) induced naive mouse proliferate and secrete IL-10 IL-6. addition, HSP60-treated up-regulated expression of MHC class II accessory molecules CD69, CD40, B7-2. tested functional...
Soluble 60 kDa heat shock protein (HSP60) activates macrophages via TLR4. We now report that soluble HSP60 T cells the innate receptor TLR2. activated cell adhesion to fibronectin a degree similar other activators: IL-2, SDF-1alpha, and RANTES. type state of activation was important; nonactivated CD45RA+ IL-2-activated CD45RO+ responded optimally (1 h) at low concentrations (0.1-1 ng/ml), but required higher (approximately 1 microg/ml) HSP60. signaling inhibited specifically by monoclonal...
Abstract LPS, a molecule produced by Gram-negative bacteria, is known to activate both innate immune cells such as macrophages and adaptive B via TLR4 signaling. Although also expressed on T cells, LPS was observed not affect cell proliferation or cytokine secretion. We now report, however, that can induce human adhere fibronectin This response confirmed in mouse cells; functional MyD88 were required, but from TLR2 knockout mice could respond LPS. The depended protein kinase C signaling...
Abstract Targeted inhibition of Rho-associated kinase (ROCK)2 downregulates the proinflammatory T cell response while increasing regulatory arm immune in animals models autoimmunity and Th17-skewing human culture vitro. In this study, we report that oral administration a selective ROCK2 inhibitor, KD025, reduces psoriasis area severity index scores by 50% from baseline 46% patients with vulgaris, it decreases epidermal thickness as well infiltration skin. We observed significant reductions...
Fibrosis, the primary cause of morbidity in chronic liver disease, is induced by pro-inflammatory cytokines, immune cell infiltrates, and tissue resident cells that drive excessive myofibroblast activation, collagen production, scarring. Rho-associated kinase 2 (ROCK2) regulates key pro-fibrotic pathways involved both inflammatory reactions altered extracellular matrix remodelling, implicating this pathway as a potential therapeutic target.We used thioacetamide-induced fibrosis model to...
Abstract Extracellular heat shock protein 60 (HSP60) has been considered a proinflammatory danger signal. Yet, HSP60 can also down-regulate experimental immune arthritis and diabetes models by specific inhibition of Th1-like responses. We now report that in vitro differentially modulates the expression Th1/Th2 transcription factors human T cells: down-regulates T-bet, NF-κB, NFATp up-regulates GATA-3, leading to decreased secretion TNF-α IFN-γ enhanced IL-10. These effects depended on TLR2...
MINI REVIEW article Front. Immunol., 25 July 2013Sec. Immunological Tolerance and Regulation Volume 4 - 2013 | https://doi.org/10.3389/fimmu.2013.00211
Rho-associated kinase 2 (ROCK2) determines the balance between human T helper 17 (TH17) cells and regulatory (Treg) cells. We investigated its role in generation of follicular (TFH) cells, which help to generate antibody-producing B under normal autoimmune conditions. Inhibiting ROCK2 or peripheral blood mononuclear from patients with active systemic lupus erythematosus (SLE) decreased number function TFH induced by activation ex vivo. Moreover, inhibition activity abundance transcriptional...
Traumatic brain injury (TBI) results in prolonged and non-resolving activation of microglia. Forced turnover these cells during the acute phase TBI aids recovery, but cell-intrinsic pathways that underpin pro-repair phenotype repopulating microglia remain unclear. Here, we show selective targeting ROCK2 with small molecule inhibitor KD025 impairs proliferative response after as well genetically induced treatment abolished substantial neuroprotective cognitive benefits conferred by microglia,...
Targeting the JAK/STAT pathway has emerged as a key therapeutic strategy for managing Rheumatoid Arthritis (RA). JAK inhibitors suppress cytokine-mediated signaling, including critical IL-6/STAT3 axis, thereby effectively targeting different aspects of pathological process. However, despite their clinical efficacy, subset RA patients remains refractory to inhibition, underscoring need alternative approaches. Here, we identify novel JAK-independent mechanism STAT3 activation, which is...
Abstract Previously, we reported that treatment of T cells with the 60-kDa heat shock protein (HSP60) inhibits chemotaxis. We now report purified human recombinant HSP60 or its biologically active peptide p277 up-regulates suppressor cytokine signaling (SOCS)3 expression via TLR2 and STAT3 activation. SOCS3, in turn, downstream effects stromal cell-derived-1α (CXCL12)-CXCR4 interaction in: 1) phosphorylation ERK1/2, Pyk2, AKT, myosin L chain, required for cell adhesion migration; 2)...
Foxp3 + CD4 CD25 high regulatory T cell (Treg) suppression of inflammation depends on T-cell receptor-mediated Nuclear Factor Activated cells c1 (NFATc1) activation with reduced Akt activity. We investigated the role scaffold protein Disc large homolog 1 (Dlgh1) in linking receptor to this unique signaling outcome. The Treg immunological synapse (IS) recruited fourfold more Dlgh1 than conventional IS. Tregs isolated from patients active rheumatoid arthritis, or treated tumor necrosis...
Rho-associated coiled-coil kinase (ROCK)2 targeting down-regulates autoimmune responses in animal models and patients, however the underlying molecular mechanism is still an enigma. We report that ROCK2 binds phosphorylated-STAT3 its activity controls formation of ROCK2/STAT3/JAK2 complex optimal STAT3 phosphorylation human CD4+ T cells during helper 17 (TH17)-skewing. Moreover, chromatin-immunoprecipitation sequencing (ChIP-seq) analysis revealed that, genome-wide, about 70% peaks...