The role of type I interferons and other cytokines in dermatomyositis.
Autoantibodies/immunology; Biological; Cytokines; Dermatomyositis; Dermatomyositis/*immunology/physiopathology/therapy; Humans; Inflammatory myopathy; Interferon Type I/*metabolism; Models; Pathogenesis; Signal Transduction; Type I interferons
Much work has been done to unveil the mechanisms behind the pathogenesis of dermatomyositis (DM) - mainly those involving certain pathogenic cytokines, termed "pathokines" as the principal cytokines involved. Recently, it has become clear that a group of cytokines known as type I interferons (IFN-Is) play a significant role in the development of DM. We review the literature published between 1946 and 2014 using an Ovid Medline database search to provide an update on the role of IFN-Is and other cytokines in the pathogenesis of DM. We provide information about the genes and proteins induced by IFN-Is and potential mechanisms by which these downstream products relate to clinical disease activity. We also explore findings of other autoimmune phenomena that may contribute to disease onset and activity including T-helper 17 (Th17) cells and associated interleukins, as well as autoantibodies. Finally, we provide a brief update on current treatment options for DM as well as some new immunomodulatory treatment modalities in development.
Arshanapalli Ashish; Shah Mihir; Veerula Vindhya; Somani Ally-Khan
Cytokine
2015
2015-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.cyto.2014.11.026" target="_blank" rel="noreferrer noopener">10.1016/j.cyto.2014.11.026</a>
Genetically enhancing the expression of chemokine domain of CX3CL1 fails to prevent tau pathology in mouse models of tauopathy.
Alzheimer's disease; Animal; Animals; Antigens; Biological; Calcium Binding Proteins – Metabolism; Calcium-Binding Proteins/metabolism; Cells – Drug Effects; Cells – Metabolism; Cells – Pathology; Chemokine CX3CL1/*genetics/metabolism; Cognition Disorders – Etiology; Cognition Disorders/etiology; CX3CL1; CX3CR1; Cytokines; Cytokines – Metabolism; Cytokines/metabolism; Differentiation/genetics/metabolism; Disease Models; Gene Expression Regulation/drug effects/*genetics; Genes; Genes – Drug Effects; Learning; Lipopolysaccharides; Lipopolysaccharides/toxicity; Maze Learning; Mice; Microfilament Proteins – Metabolism; Microfilament Proteins/metabolism; Microglia; Microglia/drug effects/*metabolism/pathology; Models; Mutation; Mutation/genetics; Nerve Tissue Proteins; Nerve Tissue Proteins – Metabolism; Neurodegenerative Diseases; Neurodegenerative Diseases – Complications; Neurodegenerative Diseases – Pathology; Neuroinflammation; Surface; Surface – Metabolism; Tau; tau Proteins/genetics/metabolism; Tauopathies; Tauopathies/complications/genetics/*pathology; Transgenic
BACKGROUND: Fractalkine (CX3CL1) and its receptor (CX3CR1) play an important role in regulating microglial function. We have previously shown that Cx3cr1 deficiency exacerbated tau pathology and led to cognitive impairment. However, it is still unclear if the chemokine domain of the ligand CX3CL1 is essential in regulating neuronal tau pathology. METHODS: We used transgenic mice lacking endogenous Cx3cl1 (Cx3cl1(-/-)) and expressing only obligatory soluble form (with only chemokine domain) and lacking the mucin stalk of CX3CL1 (referred to as Cx3cl1(105Delta) mice) to assess tau pathology and behavioral function in both lipopolysaccharide (LPS) and genetic (hTau) mouse models of tauopathy. RESULTS: First, increased basal tau levels accompanied microglial activation in Cx3cl1(105Delta) mice compared to control groups. Second, increased CD45(+) and F4/80(+) neuroinflammation and tau phosphorylation were observed in LPS, hTau/Cx3cl1(-/-), and hTau/Cx3cl1(105Delta) mouse models of tau pathology, which correlated with impaired spatial learning. Finally, microglial cell surface expression of CX3CR1 was reduced in Cx3cl1(105Delta) mice, suggesting enhanced fractalkine receptor internalization (mimicking Cx3cr1 deletion), which likely contributes to the elevated tau pathology. CONCLUSIONS: Collectively, our data suggest that overexpression of only chemokine domain of CX3CL1 does not protect against tau pathology.
Bemiller Shane M; Maphis Nicole M; Formica Shane V; Wilson Gina N; Miller Crystal M; Xu Guixiang; Kokiko-Cochran Olga N; Kim Ki-Wook; Jung Steffen; Cannon Judy L; Crish Samuel D; Cardona Astrid E; Lamb Bruce T; Bhaskar Kiran
Journal of neuroinflammation
2018
2018-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1186/s12974-018-1310-6" target="_blank" rel="noreferrer noopener">10.1186/s12974-018-1310-6</a>
CEL-1000 - a peptide with adjuvant activity or Th1 immune responses
Research & Experimental Medicine; Immunology; cytokines; antibodies; beta-2-microglobulin; vaccines; dna; antigens; CEL-1000; epitope; gamma interferon; IgG2a antibodies; liposomes
CEL-1000 (derG, DGQEEKAGVVSTGLIGGG) is a small immunomodulatory peptide which delivers demonstrated protective activity in two infectious disease challenge models (HSV and malaria) and an allogenic tumor vaccine model. CEL-1000 and other activators (defensin-beta, CpG ODN, and imiquimod) of the innate immune system promote IFN-gamma-associated protective responses. CEL-1000 is an improved form of peptide G (a peptide from human MHC II beta chain second domain, aa 135-149) known to enhance immune responses of other immunogenic peptides. Since defensin-P, CpG ODN, and imiquimod have been shown to possess adjuvant activity, we investigated the adjuvant effect of peptide G and CEL-1000 as conjugates with HIV and malaria peptides. Antibody titers and isotypes were evaluated on serum taken from select days following immunization. Results for CEL-1000 and G peptide conjugates were compared with results for KLH conjugates of the same HIV peptide from the p 17 molecule (87-116) referred to as HGP-30. Studies demonstrated that comparable titers were seen on day 28, 42, 63, and 77 with either G or KLH-HGP-30 peptide conjugates. In another study, CEL-1000 conjugates (CEL-1000-HGP-30) demonstrated a 4-10-fold higher titer antibody response than seen with several other peptide conjugates of the same HGP-30 peptide. Improved adjuvant activity of CEL-1000 in peptide conjugates was also demonstrated by a shift in the antibody isotypes toward a Th1 response (IgG2a). The IgG2a/IgG1, ratio for G-HGP-30 HIV or KLH-HGP-30 HIV conjugates were lower than for the CEL-1000-HGP-30 HIV conjugate. A similar favoring of the IgG2a/IgG1 ratio was seen for a malaria peptide conjugate (CEL-1000-SF/GF) compared to the un-conjugated peptide (SF-GF). CEL-1000 also showed adjuvant activity in an allogenic tumor vaccine model. As expected for an adjuvant, CEL-1000 or G does not induce detectable self-directed or cross reactive antibodies. CEL-1000 is currently being investigated for use as an adjuvant with conventional vaccines. It is expected that IgG2a antibodies would be preferably generated by CEL-1000 adjuvancy and could enhance in vivo clearance of antigens or pathogens. (C) 2004 Elsevier Ltd. All rights reserved.
Charoenvit Y; Goel N; Whelan M; Rosenthal K S; Zimmerman D H
Vaccine
2004
2004-06
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.vaccine.2003.11.062" target="_blank" rel="noreferrer noopener">10.1016/j.vaccine.2003.11.062</a>
Impact Of Parturition On Chemokine Homing Factor Expression In The Vaginal Distention Model Of Stress Urinary Incontinence
animal-model; cells; cytokines; deficiency; delivery; female; obstetric; pregnancy; rats; simulated childbirth injuries; urethra; urogenital organs; Urology & Nephrology; vagina; women; wounds and injuries
Purpose: Human childbirth simulated by vaginal distention is known to increase the expression of chemokines and receptors involved in stem cell homing and tissue repair. We hypothesized that pregnancy and parturition in rats contributes to the expression of chemokines and receptors after vaginal distention. Materials and Methods: We used 72 age matched female Lewis rats, including virgin rats with and without vaginal distention, and delivered rats with and without vaginal distention. Each rat was sacrificed immediately, or 3 or 7 days after vaginal distention and/or parturition, and the urethra was harvested. Relative expression of chemokines and receptors was determined by real-time polymerase chain reaction. Mixed models were used with the Bonferroni correction for multiple comparisons. Results: Vaginal distention up-regulated urethral expression of CCL7 immediately after injury in virgin and postpartum rats. Hypoxia inducible factor-1 alpha and vascular endothelial growth factor were up-regulated only in virgin rats immediately after vaginal distention. CD191 expression was immediately up-regulated in postpartum rats without vaginal distention compared to virgin rats without vaginal distention. CD195 was up-regulated in virgin rats 3 days after vaginal distention compared to virgin rats without vaginal distention. CD193 and CXCR4 showed delayed up-regulation in virgin rats 7 days after vaginal distention. CXCL12 was up-regulated in virgin rats 3 days after vaginal distention compared to immediately after vaginal distention. Interleukin-8 and CD192 showed no differential expression. Conclusions: Vaginal distention results in up-regulation of the chemokines and receptors expressed during tissue injury, which may facilitate the spontaneous functional recovery previously noted. Pregnancy and delivery up-regulated CD191 and attenuated the expression of hypoxia inducible factor-1 alpha and vascular endothelial growth factor in the setting of vaginal distention, likely by decreasing hypoxia.
Lenis A T; Kuang M; Woo L L; Hijaz A; Penn M S; Butler R S; Rackley R; Damaser M S; Wood H M
Journal of Urology
2013
2013-04
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.juro.2012.09.096" target="_blank" rel="noreferrer noopener">10.1016/j.juro.2012.09.096</a>
miR-145 is differentially regulated by TGF-ss 1 and ischaemia and targets Disabled-2 expression and wnt/ss-catenin activity
gene-expression; Myocardial infarction; Cell Biology; Myocardial infarction; Research & Experimental Medicine; stem-cells; binding; pathway; cytokines; growth factors; c-myc; cell-differentiation; dab2; epithelial ovarian-cancer; myosin-vi; nasopharyngeal carcinoma
The effect of wnt/beta-catenin signalling in the response to acute myocardial infarction (AMI) remains controversial. The membrane receptor adaptor protein Disabled-2 (Dab2) is a tumour suppressor protein and has a critical role in stem cell specification. We recently demonstrated that down-regulation of Dab2 regulates cardiac protein expression and wnt/beta-catenin activity in mesenchymal stem cells (MSC) in response to transforming growth factor-beta 1 (TGF-beta 1). Although Dab2 expression has been shown to have effects in stem cells and tumour suppression, the molecular mechanisms regulating this expression are still undefined. We identified putative binding sites for miR-145 in the 3'-UTR of Dab2. In MSC in culture, we observed that TGF-beta 1 treatment led to rapid and sustained up-regulation of primiR-145. Through gain and loss of function studies we demonstrate that miR-145 up-regulation was required for the down-regulation of Dab2 and increased beta-catenin activity in response to TGF-beta 1. To begin to define how Dab2 might regulate wnt/beta-catenin in the heart following AMI, we quantified myocardial Dab2 as a function of time after left anterior descending ligation. There was no significant Dab2 expression in sham-operated myocardium. Following AMI, Dab2 levels were rapidly up-regulated in cardiac myocytes in the infarct border zone. The increase in cardiac myocyte Dab2 expression correlated with the rapid and sustained down-regulation of myocardial primiR-145 expression following AMI. Our data demonstrate a novel and critical role for miR-145 expression as a regulator of Dab2 expression and beta-catenin activity in response to TGF-beta 1 and hypoxia.
Mayorga M E; Penn M S
Journal of Cellular and Molecular Medicine
2012
2012-05
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1111/j.1582-4934.2011.01385.x" target="_blank" rel="noreferrer noopener">10.1111/j.1582-4934.2011.01385.x</a>
Early pro-inflammatory cytokine elevations in the DBA/2J mouse model of glaucoma
Aging; axonal-transport; axoplasmic-transport; Cytokines; fibroblast-growth-factor; gene-expression; glaucoma; Immunology; inflammation; Intraocular pressure; Intraocular pressure; necrosis-factor-alpha; neurodegeneration; Neurosciences & Neurology; ocular hypertension; optic-nerve head; retinal ganglion-cells; tnf-alpha
Background: Neuroinflammation-astrogliosis, microglial activation, and changes in cytokine signaling-is a prominent feature of neurodegenerative disorders. Glaucoma is a group of chronic neurodegenerative conditions that make up the leading cause of irreversible blindness worldwide. Neuroinflammation has been postulated to play a significant role in the pathogenesis and progression of glaucomatous neurodegeneration. Though much is known regarding inflammation in the eye in glaucoma, little is known about cytokine activity outside of the retina where pathologies develop early. Methods: We traced the primary visual projection from the eye to the superior colliculus (SC) in DBA/2J and DBA/2J. Gpnmb(+) (control) mice using the anterograde tracer cholera toxin-B (CTB) to assay axonal transport deficits. Forty-eight hours later, visual structures were microdissected from fresh tissue based on transport outcome. Using magnetic bead multiplexing assays, we measured levels of 20 cytokines in the retina, proximal and distal optic nerves, CTB-positive and negative SC subdivisions, cerebellum, and serum at different ages representing different stages of pathology. Results: Pro-and anti-inflammatory cytokine levels in mice often changed in the same direction based on strain, age, and tissue. Significant elevations in retinal pro-inflammatory cytokines were observed in young DBA/2J mice compared to controls, followed by an age-dependent decrease in the DBA/2J mice. Proximal optic nerve of young DBA/2J mice showed a 50 % or greater decrease in levels of certain cytokines compared to older DBA/2J cohorts and controls, while both proximal and distal optic nerve of DBA/2Js showed elevations in IL-1 beta at all ages compared to controls. Pro-inflammatory cytokine IL-6 levels varied in accordance with transport outcome in the SC: IL-6 was elevated 44-80 % in glaucomatous DBA/2J collicular regions deficient in anterograde transport from retinal ganglion cells (RGCs) compared to areas with intact transport. Conclusion: Dysregulation of cytokine signaling in the RGC projection of DBA/2J mice was evident early in distal retinal targets, well before intraocular pressure elevation or axonal degeneration begins.
Wilson G N; Inman D M; Denger-Crish C M; Smith M A; Crish S D
Journal of Neuroinflammation
2015
2015-09
Journal Article
<a href="http://doi.org/10.1186/s12974-015-0399-0" target="_blank" rel="noreferrer noopener">10.1186/s12974-015-0399-0</a>