scholarly journals Cytokines, Genetic Lesions and Signaling Pathways in Anaplastic Large Cell Lymphomas

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4256
Author(s):  
Jean-Philippe Merlio ◽  
Marshall E. Kadin
Keyword(s):  
Signaling Pathways ◽  
Clinical Presentation ◽  
Large Cell ◽  
Skin Lesions ◽  
Lymphoid Cells ◽  
The Other ◽  
Cytokine Receptors ◽  
Epidermal Hyperplasia ◽  
Activated T Cells ◽  
Ifn Γ

ALCL is a tumor of activated T cells and possibly innate lymphoid cells with several subtypes according to clinical presentation and genetic lesions. On one hand, the expression of transcription factors and cytokine receptors triggers signaling pathways. On the other hand, ALCL tumor cells also produce many proteins including chemokines, cytokines and growth factors that affect patient symptoms. Examples are accumulation of granulocytes stimulated by IL-8, IL-17, IL-9 and IL-13; epidermal hyperplasia and psoriasis-like skin lesions due to IL-22; and fever and weight loss in response to IL-6 and IFN-γ. In this review, we focus on the biology of the main ALCL subtypes as the identification of signaling pathways and ALCL-derived cytokines offers opportunities for targeted therapies.

Suppressor of cytokine signaling-1 in T cells and macrophages is critical for preventing lethal inflammation

Blood ◽  
2005 ◽  
Vol 106 (5) ◽  
pp. 1668-1675 ◽  
Author(s):  
Mark M. W. Chong ◽  
Donald Metcalf ◽  
Emma Jamieson ◽  
Warren S. Alexander ◽  
Thomas W. H. Kay
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Disease ◽  
Lymphoid Cells ◽  
Interleukin 12 ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Cytokine Network ◽  
Activated T Cells ◽  
Ifn Γ

Abstract The balance between pro- and anti-inflammatory cytokines modulates inflammation. Intracellular inhibitors of signaling, in turn, contribute to the negative regulation of cytokines. One of these inhibitors is suppressor of cytokine signaling-1 (SOCS-1). Socs1-/- mice die by 3 weeks of age with inflammation and fatty necrosis of the liver. Here, cre/loxP deletion of Socs1 was used to investigate the contribution of specific cells/tissues to inflammatory disease. Mice with SOCS-1 deficiency in myeloid and lymphoid cells, but not lymphoid alone, became ill at 50 to 250 days of age. These mice developed splenomegaly and T-cell/macrophage infiltration of many organs, including liver, lung, pancreas, and muscle. There were also abnormally high levels of the proinflammatory cytokines interferon γ (IFN-γ), tumor necrosis factor (TNF), and interleukin-12 (IL-12), and activated T cells circulating in these mice. Socs1null T cells were found to be hypersensitive to multiple cytokines, including IL-1, IL-2, and IL-12, resulting in IFN-γ production without requiring T-cell receptor (TCR) ligation. Additionally, Socs1null macrophages produced excessive amounts of IL-12 and TNF in response to other cytokines, including IFN-γ. A dysregulated cytokine network between T cells and macrophages is thus associated with this inflammatory disease. These findings indicate that SOCS-1 is critical in both T cells and macrophages for preventing uncontrolled inflammation. (Blood. 2005;106:1668-1675)

scholarly journals Childhood Ki-1 lymphoma presenting with skin lesions and peripheral lymphadenopathy

Blood ◽  
1986 ◽  
Vol 68 (5) ◽  
pp. 1042-1049 ◽  
Author(s):  
ME Kadin ◽  
D Sako ◽  
N Berliner ◽  
W Franklin ◽  
B Woda ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Cells ◽  
Large Cell ◽  
Cell Receptor ◽  
Skin Lesions ◽  
Lymphoid Cells ◽  
Nonspecific Esterase ◽  
Leukocyte Antigen ◽  
Common Leukocyte Antigen ◽  
Beta Chain Genes

We describe a large-cell lymphoma of activated lymphoid cells in six children and adolescents. The presenting clinical features of regressing skin lesions and peripheral lymphadenopathy, sinus infiltration of lymph nodes, and infrequent tumor cell erythrophagocytosis resulted in initial diagnoses of malignant or regressing atypical histiocytosis in five cases. Binucleate and multinucleate tumor cells, sometimes with prominent eosinophilic nucleoli, resembled Reed-Sternberg (RS) cells and occasionally were found in a cytoarchitectural milieu that was consistent with a diagnosis of Hodgkin's disease (HD). The tumor cells did in fact express the HD-associated antigen Ki-1, but unlike most types of HD, the RS-like cells expressed common leukocyte antigen and were negative for Leu-M1. A T cell origin for the malignant cells was demonstrated with monoclonal antibodies in two cases, by focal staining for nonspecific esterase in one case, and by rearrangement of the beta- chain genes for the T cell receptor in a fourth case. These studies provide further evidence that some cases previously interpreted as malignant or regressing atypical histiocytosis and some types of HD are actually T cell disorders.

scholarly journals Childhood Ki-1 lymphoma presenting with skin lesions and peripheral lymphadenopathy

Blood ◽  
1986 ◽  
Vol 68 (5) ◽  
pp. 1042-1049 ◽  
Author(s):  
ME Kadin ◽  
D Sako ◽  
N Berliner ◽  
W Franklin ◽  
B Woda ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Cells ◽  
Large Cell ◽  
Cell Receptor ◽  
Skin Lesions ◽  
Lymphoid Cells ◽  
Nonspecific Esterase ◽  
Leukocyte Antigen ◽  
Common Leukocyte Antigen ◽  
Beta Chain Genes

Abstract We describe a large-cell lymphoma of activated lymphoid cells in six children and adolescents. The presenting clinical features of regressing skin lesions and peripheral lymphadenopathy, sinus infiltration of lymph nodes, and infrequent tumor cell erythrophagocytosis resulted in initial diagnoses of malignant or regressing atypical histiocytosis in five cases. Binucleate and multinucleate tumor cells, sometimes with prominent eosinophilic nucleoli, resembled Reed-Sternberg (RS) cells and occasionally were found in a cytoarchitectural milieu that was consistent with a diagnosis of Hodgkin's disease (HD). The tumor cells did in fact express the HD-associated antigen Ki-1, but unlike most types of HD, the RS-like cells expressed common leukocyte antigen and were negative for Leu-M1. A T cell origin for the malignant cells was demonstrated with monoclonal antibodies in two cases, by focal staining for nonspecific esterase in one case, and by rearrangement of the beta- chain genes for the T cell receptor in a fourth case. These studies provide further evidence that some cases previously interpreted as malignant or regressing atypical histiocytosis and some types of HD are actually T cell disorders.

scholarly journals Impressic Acid Ameliorates Atopic Dermatitis-Like Skin Lesions by Inhibiting ERK1/2-Mediated Phosphorylation of NF-κB and STAT1

2021 ◽  
Vol 22 (5) ◽  
pp. 2334
Author(s):  
Jae Ho Choi ◽  
Gi Ho Lee ◽  
Sun Woo Jin ◽  
Ji Yeon Kim ◽  
Yong Pil Hwang ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Skin Lesions ◽  
Histopathological Analysis ◽  
Mrna Levels ◽  
Chemokine Production ◽  
Dermal Thickness ◽  
Skin Symptoms ◽  
Tnf Α ◽  
Ifn Γ ◽  
In Cells

Impressic acid (IPA), a lupane-type triterpenoid from Acanthopanax koreanum, has many pharmacological activities, including the attenuation of vascular endothelium dysfunction, cartilage destruction, and inflammatory diseases, but its influence on atopic dermatitis (AD)-like skin lesions is unknown. Therefore, we investigated the suppressive effect of IPA on 2,4-dinitrochlorobenzene (DNCB)-induced AD-like skin symptoms in mice and the underlying mechanisms in cells. IPA attenuated the DNCB-induced increase in the serum concentrations of IgE and thymic stromal lymphopoietin (TSLP), and in the mRNA levels of thymus and activation regulated chemokine(TARC), macrophage derived chemokine (MDC), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-13 (IL-13), tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) in mice. Histopathological analysis showed that IPA reduced the epidermal/dermal thickness and inflammatory and mast cell infiltration of ear tissue. In addition, IPA attenuated the phosphorylation of NF-κB and IκBα, and the degradation of IκBα in ear lesions. Furthermore, IPA treatment suppressed TNF-α/IFN-γ-induced TARC expression by inhibiting the NF-κB activation in cells. Phosphorylation of extracellular signalregulated protein kinase (ERK1/2) and the signal transducer and activator of transcription 1 (STAT1), the upstream signaling proteins, was reduced by IPA treatment in HaCaT cells. In conclusion, IPA ameliorated AD-like skin symptoms by regulating cytokine and chemokine production and so has therapeutic potential for AD-like skin lesions.

scholarly journals Suppressor of cytokine signaling-1 mimetic peptides attenuate lymphocyte activation in the MRL/lpr mouse autoimmune model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jatin Sharma ◽  
Teresa D. Collins ◽  
Tracoyia Roach ◽  
Shiwangi Mishra ◽  
Brandon K. Lam ◽  
...  
Keyword(s):  
Intraperitoneal Administration ◽  
Lymphocyte Activation ◽  
Signal Propagation ◽  
Skin Lesions ◽  
Effector Memory ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Autoantibody Production ◽  
Ifn Γ

AbstractAutoimmune diseases are driven largely by a pathogenic cytokine milieu produced by aberrantly activated lymphocytes. Many cytokines, including interferon gamma (IFN-γ), utilize the JAK/STAT pathway for signal propagation. Suppressor of Cytokine Signaling-1 (SOCS1) is an inducible, intracellular protein that regulates IFN-γ signaling by dampening JAK/STAT signaling. Using Fas deficient, MRL/MpJ-Faslpr/J (MRL/lpr) mice, which develop lupus-like disease spontaneously, we tested the hypothesis that a peptide mimic of the SOCS1 kinase inhibitory region (SOCS1-KIR) would inhibit lymphocyte activation and modulate lupus-associated pathologies. Consistent with in vitro studies, SOCS1-KIR intraperitoneal administration reduced the frequency, activation, and cytokine production of memory CD8+ and CD4+ T lymphocytes within the peripheral blood, spleen, and lymph nodes. In addition, SOCS1-KIR administration reduced lymphadenopathy, severity of skin lesions, autoantibody production, and modestly reduced kidney pathology. On a cellular level, peritoneal SOCS1-KIR administration enhanced Foxp3 expression in total splenic and follicular regulatory T cells, reduced the effector memory/naïve T lymphocyte ratio for both CD4+ and CD8+ cells, and reduced the frequency of GL7+ germinal center enriched B cells. Together, these data show that SOCS1-KIR treatment reduced auto-reactive lymphocyte effector functions and suggest that therapeutic targeting of the SOCS1 pathway through peptide administration may have efficacy in mitigating autoimmune pathologies.

scholarly journals Gomisin M2 Ameliorates Atopic Dermatitis-like Skin Lesions via Inhibition of STAT1 and NF-κB Activation in 2,4-Dinitrochlorobenzene/Dermatophagoides farinae Extract-Induced BALB/c Mice

Molecules ◽  
2021 ◽  
Vol 26 (15) ◽  
pp. 4409
Author(s):  
Jinjoo Kang ◽  
Soyoung Lee ◽  
Namkyung Kim ◽  
Hima Dhakal ◽  
Taeg-Kyu Kwon ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Oral Administration ◽  
Skin Diseases ◽  
Nuclear Translocation ◽  
Skin Lesions ◽  
Biologically Active ◽  
Therapeutic Effects ◽  
Dermatophagoides Farinae ◽  
Tnf Α ◽  
Ifn Γ

The extracts of Schisandra chinensis (Turcz.) Baill. (Schisandraceae) have various therapeutic effects, including inflammation and allergy. In this study, gomisin M2 (GM2) was isolated from S. chinensis and its beneficial effects were assessed against atopic dermatitis (AD). We evaluated the therapeutic effects of GM2 on 2,4-dinitrochlorobenzene (DNCB) and Dermatophagoides farinae extract (DFE)-induced AD-like skin lesions with BALB/c mice ears and within the tumor necrosis factor (TNF)-α and interferon (IFN)-γ-stimulated keratinocytes. The oral administration of GM2 resulted in reduced epidermal and dermal thickness, infiltration of tissue eosinophils, mast cells, and helper T cells in AD-like lesions. GM2 suppressed the expression of IL-1β, IL-4, IL-5, IL-6, IL-12a, and TSLP in ear tissue and the expression of IFN-γ, IL-4, and IL-17A in auricular lymph nodes. GM2 also inhibited STAT1 and NF-κB phosphorylation in DNCB/DFE-induced AD-like lesions. The oral administration of GM2 reduced levels of IgE (DFE-specific and total) and IgG2a in the mice sera, as well as protein levels of IL-4, IL-6, and TSLP in ear tissues. In TNF-α/IFN-γ-stimulated keratinocytes, GM2 significantly inhibited IL-1β, IL-6, CXCL8, and CCL22 through the suppression of STAT1 phosphorylation and the nuclear translocation of NF-κB. Taken together, these results indicate that GM2 is a biologically active compound that exhibits inhibitory effects on skin inflammation and suggests that GM2 might serve as a remedy in inflammatory skin diseases, specifically on AD.

scholarly journals Camu-Camu Fruit Extract Inhibits Oxidative Stress and Inflammatory Responses by Regulating NFAT and Nrf2 Signaling Pathways in High Glucose-Induced Human Keratinocytes

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3174
Author(s):  
Nhung Quynh Do ◽  
Shengdao Zheng ◽  
Bom Park ◽  
Quynh T. N. Nguyen ◽  
Bo-Ram Choi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathways ◽  
High Glucose ◽  
Skin Diseases ◽  
Inflammatory Responses ◽  
Human Keratinocytes ◽  
Related Factor ◽  
Nuclear Factor ◽  
Fruit Extract ◽  
Activated T Cells

Myrciaria dubia (HBK) McVaugh (camu-camu) belongs to the family Myrtaceae. Although camu-camu has received a great deal of attention for its potential pharmacological activities, there is little information on the anti-oxidative stress and anti-inflammatory effects of camu-camu fruit in skin diseases. In the present study, we investigated the preventative effect of 70% ethanol camu-camu fruit extract against high glucose-induced human keratinocytes. High glucose-induced overproduction of reactive oxygen species (ROS) was inhibited by camu-camu fruit treatment. In response to ROS reduction, camu-camu fruit modulated the mitogen-activated protein kinases (MAPK)/activator protein-1 (AP-1), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and nuclear factor of activated T cells (NFAT) signaling pathways related to inflammation by downregulating the expression of proinflammatory cytokines and chemokines. Furthermore, camu-camu fruit treatment activated the expression of nuclear factor E2-related factor 2 (Nrf2) and subsequently increased the NAD(P)H:quinone oxidoreductase1 (NQO1) expression to protect keratinocytes against high-glucose-induced oxidative stress. These results indicate that camu-camu fruit is a promising material for preventing oxidative stress and skin inflammation induced by high glucose level.

Peripheral T-cell lymphomas unspecified presenting in the skin: analysis of prognostic factors in a group of 82 patients

Blood ◽  
2003 ◽  
Vol 102 (6) ◽  
pp. 2213-2219 ◽  
Author(s):  
Marcel W. Bekkenk ◽  
Maarten H. Vermeer ◽  
Patty M. Jansen ◽  
Ariënne M. W. van Marion ◽  
Marijke R. Canninga-van Dijk ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Size ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Skin Lesions ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
T Cell Lymphomas ◽  
Nor Phenotype ◽  
Peripheral T Cell Lymphomas

Abstract In the present study the clinicopathologic and immunophenotypic features of 82 patients with a CD30– peripheral T-cell lymphoma, unspecified, presenting in the skin were evaluated. The purpose of this study was to find out whether subdivision of these lymphomas on the basis of cell size, phenotype, or presentation with only skin lesions is clinically relevant. The study group included 46 primary cutaneous CD30– large cell lymphomas and 17 small/medium-sized T-cell lymphomas as well as 17 peripheral T-cell lymphomas with both skin and extracutaneous disease at the time of diagnosis. Patients with primary cutaneous small- or medium-sized T-cell lymphomas had a significantly better prognosis (5-year-overall survival, 45%) than patients with primary cutaneous CD30– large T-cell lymphomas (12%) and patients presenting with concurrent extracutaneous disease (12%). The favorable prognosis in this group with primary cutaneous small- or medium-sized T-cell lymphomas was particularly found in patients presenting with localized skin lesions expressing a CD3+CD4+CD8– phenotype. In the primary cutaneous T-cell lymphoma (CTCL) group and in the concurrent group, neither extent of skin lesions nor phenotype had any effect on survival. Our results indicate that peripheral T-cell lymphomas, unspecified, presenting in the skin have an unfavorable prognosis, irrespective of the presence or absence of extracutaneous disease at the time of diagnosis, cell size, and expression of a CD4+ or CD8+ phenotype. The only exception was a group of primary cutaneous small- or medium-sized pleomorphic CTCLs with a CD3+CD4+CD8– phenotype and presenting with localized skin lesions.

scholarly journals Integration of Calcium and Cyclic AMP Signaling Pathways by 14-3-3

2000 ◽  
Vol 20 (2) ◽  
pp. 702-712 ◽  
Author(s):  
Chi-Wing Chow ◽  
Roger J. Davis
Keyword(s):  
T Cells ◽  
Cyclic Amp ◽  
Signaling Pathways ◽  
Interleukin 2 ◽  
Camp Signaling ◽  
Phosphorylation Sites ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Transcription Activity ◽  
Kinase A

ABSTRACT Calcium-stimulated nuclear factor of activated T cells (NFAT) transcription activity at the interleukin-2 promoter is negatively regulated by cyclic AMP (cAMP). This effect of cAMP is mediated, in part, by protein kinase A phosphorylation of NFAT. The mechanism of regulation involves the creation of a phosphorylation-dependent binding site for 14-3-3. Decreased NFAT phosphorylation caused by the calcium-stimulated phosphatase calcineurin, or mutation of the PKA phosphorylation sites, disrupted 14-3-3 binding and increased NFAT transcription activity. In contrast, NFAT phosphorylation caused by cAMP increased 14-3-3 binding and reduced NFAT transcription activity. The regulated interaction between NFAT and 14-3-3 provides a mechanism for the integration of calcium and cAMP signaling pathways.

scholarly journals Hepatic DR5 Induces Apoptosis and Limits Adenovirus Gene Therapy Product Expression in the Liver

2002 ◽  
Vol 76 (11) ◽  
pp. 5692-5700 ◽  
Author(s):  
Huang-Ge Zhang ◽  
Jinfu Xie ◽  
Liang Xu ◽  
Pingar Yang ◽  
Xin Xu ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
Transgene Expression ◽  
Cell Activation ◽  
Nk Cell ◽  
Death Domain ◽  
Activated T Cells ◽  
Tnf Α ◽  
Product Expression ◽  
Ifn Γ

ABSTRACT A major limitation of adenovirus (Ad) gene therapy product expression in the liver is subsequent elimination of the hepatocytes expressing the gene therapy product. This elimination is caused by both necrosis and apoptosis related to the innate and cell-mediated immune response to the Ad. Apoptosis of hepatocytes can be induced by the innate immune response by signaling through death domain receptors on hepatocytes including the tumor necrosis factor alpha (TNF-α) receptor (TNFR), Fas, and death domain receptors DR4 and DR5. We have previously shown that blocking signaling through TNFR enhances and prolongs gene therapy product expression in the liver. In the present study, we constructed an Ad that produces a soluble DR5-Fc (AdsDR5), which is capable of neutralizing TNF-related apoptosis-inducing ligand (TRAIL). AdsDR5 prevents TRAIL-mediated apoptosis of CD3-activated T cells and decreases hepatocyte apoptosis after AdCMVLacZ administration and enhances the level and duration of lacZ transgene expression in the liver. In addition to blocking TRAIL and directly inhibiting apoptosis, AdsDR5 decreases production of gamma interferon (IFN-γ) and TNF-α and decreases NK cell activation, all of which limit Ad-mediated transgene expression in the liver. These results indicate that (i) AdsDR5 produces a DR5-Fc capable of neutralizing TRAIL, (ii) AdsDR5 can reduce activation of NK cells and reduce induction of IFN-γ and TNF-α after Ad administration, and (iii) administration of AdsDR5 can enhance Ad gene therapy in the liver.

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