Local pathological responses to slow-release recombinant interleukin-1, interleukin-2 and γ-interferon in the mouse and their relevance to chronic inflammatory disease

1989 ◽  
Vol 76 (3) ◽  
pp. 261-263 ◽  
Author(s):  
C. J. Dunn ◽  
M. M. Hardee ◽  
A. J. Gibbons ◽  
N. D. Staite ◽  
K. A. Richard
Keyword(s):  
Slow Release ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Interleukin 2 ◽  
Cell Formation ◽  
Chronic Inflammatory Disease ◽  
Tissue Response ◽  
Multinucleate Giant Cell ◽  
Γ Interferon

1. The present study describes the pathological responses to local administration of recombinant cytokines in subcutaneously implanted slow-release ethylene vinyl acetate (EVA) co-polymer in mice. 2. EVA-recombinant human interleukin-1β (104 units) implants induced the formation of chronic granulomatous inflammatory tissue between 4 and 7 days after implantation, characterized by predominant macrophage infiltration, neovascularization and fibrosis which persisted up to 21 days after-implantation. EVA-recombinant human interleukin-1α (104–105 units) implants induced a qualitatively similar but less intense response. 3. In contrast, recombinant human interleukin-2 (102–104 units) implants resulted in early lymphocytic vasculitis (4 days) and the development of a predominantly lymphoid lesion comprised of lymphoblasts and significant mononuclear cell proliferation by 7 days. 4. EVA-recombinant γ-interferon (103–104 units) implants failed to elicit a significant tissue response; with the exception of multinucleate giant cell formation the characteristics of these lesions closely resembled the mild fibrotic responses observed for EVA-bovine serum albumin (0.5–12.5 mg) implants. 5. These observations suggest that continuous endogenous local release of interleukin-1 or interleukin-2 in vivo is sufficient for the development of specific pathological features characterizing chronic immuno-inflammatory diseases.

scholarly journals Counter-regulation in the IKK family

2011 ◽  
Vol 434 (1) ◽  
pp. e1-e2 ◽  
Author(s):  
Luke A. J. O'Neill
Keyword(s):  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Control Mechanisms ◽  
Biochemical Journal ◽  
Regulatory Feedback Loop

The human IKK [IκB (inhibitor of NF-κB) kinase] family has four members; they are the central kinases of innate immunity. Two members, IKKα and IKKβ, the so-called canonical members, phosphoryate IκBα, leading to activation of the transcription factor NF-κB (nuclear factor κB), which controls the expression of many immune and inflammatory genes. The IKK-related proteins TBK-1 (TANK-binding kinase 1) and IKKϵ have a different substrate – IRF3 (interferon regulatory factor 3) – which regulates a different set of genes, the products of which include Type I interferons. Toll-like receptors (TLRs) such as the lipopolysaccharide receptor TLR4 or the poly(I:C) receptor TLR3 activate each of the IKKs, but the pro-inflammatory cytokine IL-1 (interleukin 1), which signals in a broadly similar way to the TLRs, has so far been shown to activate only the canonical IKKs. In this issue of the Biochemical Journal, Clark et al. bring new insights into the regulation of IKKs. They demonstrate that IL-1 is in fact able to activate IKKϵ/TBK-1, which occurs via IKKα/IKKβ. The consequence of this is not IRF3 activation, but a negative feedback effect on IKKα/IKKβ. This provides us with yet another regulatory feedback loop in a system already replete with control mechanisms. It attests yet again to the importance of keeping these innate immune pathways in check, since if they proceed uncontrolled, inflammatory diseases can occur. Importantly, this study utilized new and specific inhibitors of these kinases, suggesting that the interpretation of any effects the compound might have in vivo may be complex, since for example the inhibition of IKKϵ/TBK-1 might actually have a pro-inflammatory effect.

scholarly journals Cytokine induction of haem oxygenase mRNA in mouse liver. Interleukin 1 transcriptionally activates the haem oxygenase gene

1993 ◽  
Vol 290 (2) ◽  
pp. 343-347 ◽  
Author(s):  
M Rizzardini ◽  
M Terao ◽  
F Falciani ◽  
L Cantoni
Keyword(s):  
Interleukin 1 ◽  
Interleukin 2 ◽  
Northern Blotting ◽  
Enzymic Activity ◽  
Transcriptional Level ◽  
Protective Mechanisms ◽  
Biological Responses ◽  
Haem Oxygenase

Accumulation of the mRNA coding for haem oxygenase (HO, EC 1.14.99.3) was stimulated by treating mice with endotoxin (lipopolysaccharide, LPS; 20 micrograms/mouse intraperitoneally), suggesting that haem catabolism is a target of infection and inflammation in vivo. Therefore various cytokines, possible mediators for the biological responses to LPS, were administered intraperitoneally to mice, and the levels of HO mRNA were measured by Northern-blotting analysis using the rat HO cDNA as a probe [Shibahara, Müller, Taguchi and Yoshida (1985) Proc. Natl. Acad. Sci. U.S.A. 82, 7865-7869]. Marked induction of HO mRNA was observed 2 h after administration of interleukin 1 (IL-1) (34-fold) and tumour necrosis factor (19.5-fold) (5 micrograms/mouse), whereas interleukin 6 (6.2 micrograms/mouse) was much less active (3.5-fold) and interleukin 2 (25 micrograms/mouse) and interferon-gamma (3 micrograms/mouse) were ineffective. HO mRNA induced by the cytokines of LPS accumulated rapidly (maximum at 1-2 h after administration), preceding the elevation of HO enzymic activity. Treatment of mice with IL-1 stimulated the transcription of the HO gene by 4-fold, as assessed by in vitro nuclear-run-on assay. These results indicate that enzymic haem catabolism in the liver is a process inducible in vivo by inflammatory cytokines, which up-regulate HO synthesis at the transcriptional level. Increased removal of haem might be part of the protective mechanisms elicited by the acute-phase response, possibly to reduce the pro-oxidant state of the cell.

LILRB4 deficiency aggravates the development of atherosclerosis and plaque instability by increasing the macrophage inflammatory response via NF-κB signaling

2017 ◽  
Vol 131 (17) ◽  
pp. 2275-2288 ◽  
Author(s):  
Zhou Jiang ◽  
Juan-Juan Qin ◽  
Yaxing Zhang ◽  
Wen-Lin Cheng ◽  
Yan-Xiao Ji ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Diseases ◽  
Chronic Inflammatory Disease ◽  
Plaque Instability ◽  
Atherosclerotic Lesions ◽  
Bone Marrow Derived Cells ◽  
Underlying Mechanisms ◽  
Human And Mouse

Atherosclerosis is a chronic inflammatory disease. Leukocyte immunoglobulin-like receptor B4 (LILRB4) is associated with the pathological processes of various inflammatory diseases. However, the potential function and underlying mechanisms of LILRB4 in atherogenesis remain to be investigated. In the present study, LILRB4 expression was examined in both human and mouse atherosclerotic plaques. The effects and possible mechanisms of LILRB4 in atherogenesis and plaque instability were evaluated in LILRB4-/-ApoE-/- and ApoE-/- mice fed a high-fat diet (HFD). We found that LILRB4 was located primarily in macrophages, and its expression was up-regulated in atherosclerotic lesions from human coronary arteries and mouse aortic roots. LILRB4 deficiency significantly accelerated the development of atherosclerotic lesions and increased the instability of plaques, as evident by the increased infiltration of lipids, decreased amount of collagen components and smooth muscle cells. Moreover, LILRB4 deficiency in bone marrow derived cells promoted the development of atherosclerosis. In vivo and in vitro analyses revealed that the proinflammatory effects of LILRB4 deficiency were mediated by the increased activation of NF-κB signaling due to decreased src homolog 2 domain containing phosphatase (Shp) 1 phosphorylation. In conclusion, the present study indicates that LILRB4 deficiency promotes atherogenesis, at least partly, through reduced Shp1 phosphorylation, which subsequently enhances the NF-κB-mediated inflammatory response. Thus, targetting the ‘LILRB4-Shp1’ axis may be a novel therapeutic approach for atherosclerosis.

scholarly journals ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol–induced lipid body formation

2012 ◽  
Vol 209 (4) ◽  
pp. 807-817 ◽  
Author(s):  
Elizabeth S. Gold ◽  
Stephen A. Ramsey ◽  
Mark J. Sartain ◽  
Jyrki Selinummi ◽  
Irina Podolsky ◽  
...  
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Lipid Body ◽  
Chronic Inflammatory Disease ◽  
Intersection Point ◽  
Prediction Algorithm ◽  
Foam Cell Formation ◽  
Macrophage Foam Cell ◽  
Body Formation

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-loaded macrophages in the arterial wall. We demonstrate that macrophage lipid body formation can be induced by modified lipoproteins or by inflammatory Toll-like receptor agonists. We used an unbiased approach to study the overlap in these pathways to identify regulators that control foam cell formation and atherogenesis. An analysis method integrating epigenomic and transcriptomic datasets with a transcription factor (TF) binding site prediction algorithm suggested that the TF ATF3 may regulate macrophage foam cell formation. Indeed, we found that deletion of this TF results in increased lipid body accumulation, and that ATF3 directly regulates transcription of the gene encoding cholesterol 25-hydroxylase. We further showed that production of 25-hydroxycholesterol (25-HC) promotes macrophage foam cell formation. Finally, deletion of ATF3 in Apoe−/− mice led to in vivo increases in foam cell formation, aortic 25-HC levels, and disease progression. These results define a previously unknown role for ATF3 in controlling macrophage lipid metabolism and demonstrate that ATF3 is a key intersection point for lipid metabolic and inflammatory pathways in these cells.

scholarly journals Whole-BodyIn VivoMonitoring of Inflammatory Diseases Exploiting Human Interleukin 6-Luciferase Transgenic Mice

2015 ◽  
Vol 35 (20) ◽  
pp. 3590-3601 ◽  
Author(s):  
Makiko Hayashi ◽  
Jun Takai ◽  
Lei Yu ◽  
Hozumi Motohashi ◽  
Takashi Moriguchi ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Genetic Model ◽  
Imaging System ◽  
Inflammatory Diseases ◽  
Chronic Inflammatory Disease ◽  
Whole Body ◽  
Disease Models ◽  
Bac Clone ◽  
Inflammatory Status

Chronic inflammation underlies the pathological progression of various diseases, and thus many efforts have been made to quantitatively evaluate the inflammatory status of the diseases. In this study, we generated a highly sensitive inflammation-monitoring mouse system using a bacterial artificial chromosome (BAC) clone containing extended flanking sequences of the human interleukin 6 gene (hIL6) locus, in which the luciferase (Luc) reporter gene is integrated (hIL6-BAC-Luc). We successfully monitored lipopolysaccharide-induced systemic inflammation in various tissues of thehIL6-BAC-Lucmice using anin vivobioluminescence imaging system. When two chronic inflammatory disease models, i.e., a genetic model of atopic dermatitis and a model of experimental autoimmune encephalomyelitis (EAE), were applied to thehIL6-BAC-Lucmice, luciferase bioluminescence was specifically detected in the atopic skin lesion and central nervous system, respectively. Moreover, the Luc activities correlated well with the disease severity. Nrf2 is a master transcription factor that regulates antioxidative and detoxification enzyme genes. Upon EAE induction, the Nrf2-deficient mice crossed with thehIL6-BAC-Lucmice exhibited enhanced neurological symptoms concomitantly with robust luciferase luminescence in the neuronal tissue. Thus, whole-bodyin vivomonitoring using thehIL6-BAC-Luctransgenic system (WIM-6 system) provides a new and powerful diagnostic tool for real-timein vivomonitoring of inflammatory status in multiple different disease models.

scholarly journals TRAF5 Deficiency Accelerates Atherogenesis in Mice by Increasing Inflammatory Cell Recruitment and Foam Cell Formation

2010 ◽  
Vol 107 (6) ◽  
pp. 757-766 ◽  
Author(s):  
Anna Missiou ◽  
Philipp Rudolf ◽  
Peter Stachon ◽  
Dennis Wolf ◽  
Nerea Varo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Inflammatory Cell ◽  
Foam Cell ◽  
Interleukin 1 ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
High Cholesterol Diet ◽  
Cell Recruitment ◽  
Inflammatory Cell Recruitment

Rationale: Tumor necrosis factor receptor–associated factors (TRAFs) are cytoplasmic adaptor proteins for the TNF/interleukin-1/Toll-like receptor superfamily. Ligands of this family comprise multiple important cytokines such as TNFα, CD40L, and interleukin-1β that promote chronic inflammatory diseases such as atherosclerosis. We recently reported overexpression of TRAF5 in murine and human atheromata and that TRAF5 promotes inflammatory functions of cultured endothelial cells and macrophages. Objective: This study tested the hypothesis that TRAF5 modulates atherogenesis in vivo. Methods and Results: Surprisingly, TRAF5 −/− /LDLR −/− mice consuming a high-cholesterol diet for 18 weeks developed significantly larger atherosclerotic lesions than did TRAF5 +/+ /LDLR −/− controls. Plaques of TRAF5-deficient animals contained more lipids and macrophages, whereas smooth muscle cells and collagen remained unchanged. Deficiency of TRAF5 in endothelial cells or in leukocytes enhanced adhesion of inflammatory cells to the endothelium in dynamic adhesion assays in vitro and in murine vessels imaged by intravital microscopy in vivo. TRAF5 deficiency also increased expression of adhesion molecules and chemokines and potentiated macrophage lipid uptake and foam cell formation. These findings coincided with increased activation of JNK and appeared to be independent of TRAF2. Finally, patients with stable or acute coronary heart disease had significantly lower amounts of TRAF5 mRNA in blood compared with healthy controls. Conclusions: Unexpectedly, TRAF5 deficiency accelerates atherogenesis in mice, an effect likely mediated by increased inflammatory cell recruitment to the vessel wall and enhanced foam cell formation.

scholarly journals Discovery of a Novel MyD88 Inhibitor M20 and Its Protection Against Sepsis-Mediated Acute Lung Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiali Song ◽  
Daoxing Chen ◽  
Yingqiao Pan ◽  
Xueqin Shi ◽  
Qian Liu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Important Interaction ◽  
Receptor Signaling Pathway ◽  
Myeloid Differentiation Factor ◽  
Resonance Detection

Myeloid differentiation factor 88 (MyD88) is a hub protein in the Toll-like receptor signaling pathway, which acts as a master switch for numerous inflammatory diseases, including acute lung injury (ALI). Although this protein is considered as a crucial therapeutic target, there are currently no clinically approved MyD88-targeting drugs. Based on previous literature, here we report the discovery via computer-aided drug design (CADD) of a small molecule, M20, which functions as a novel MyD88 inhibitor to efficiently relieve lipopolysaccharide-induced inflammation both in vitro and in vivo. Computational chemistry, surface plasmon resonance detection (SPR) and biological experiments demonstrated that M20 forms an important interaction with the MyD88-Toll/interleukin-1 receptor domain and thereby inhibits the protein dimerization. Taken together, this study found a MyD88 inhibitor, M20, with a novel skeleton, which provides a crucial understanding in the development and modification of MyD88 inhibitors. Meanwhile, the favorable bioactivity of the hit compound is also conducive to the treatment of acute lung injury or other more inflammatory diseases.

scholarly journals PASylation of IL-1 receptor antagonist (IL-1Ra) retains IL-1 blockade and extends its duration in mouse urate crystal-induced peritonitis

2019 ◽  
Vol 295 (3) ◽  
pp. 868-882 ◽  
Author(s):  
Nicholas E. Powers ◽  
Benjamin Swartzwelter ◽  
Carlo Marchetti ◽  
Dennis M. de Graaf ◽  
Alexandra Lerchner ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Inflammatory Markers ◽  
Mononuclear Cells ◽  
Inflammatory Diseases ◽  
Human Peripheral Blood ◽  
Interleukin 1 ◽  
The Body ◽  
Random Coil ◽  
Peripheral Blood Mononuclear

Interleukin-1 (IL-1) is a key mediator of inflammation and immunity. Naturally-occurring IL-1 receptor antagonist (IL-1Ra) binds and blocks the IL-1 receptor-1 (IL-1R1), preventing signaling. Anakinra, a recombinant form of IL-1Ra, is used to treat a spectrum of inflammatory diseases. However, anakinra is rapidly cleared from the body and requires daily administration. To create a longer-lasting alternative, PASylated IL-1Ra (PAS–IL-1Ra) has been generated by in-frame fusion of a long, defined-length, N-terminal Pro/Ala/Ser (PAS) random-coil polypeptide with IL-1Ra. Here, we compared the efficacy of two PAS–IL-1Ra molecules, PAS600–IL-1Ra and PAS800–IL-1Ra (carrying 600 and 800 PAS residues, respectively), with that of anakinra in mice. PAS600–IL-1Ra displayed markedly extended blood plasma levels 3 days post-administration, whereas anakinra was undetectable after 24 h. We also studied PAS600–IL-1Ra and PAS800–IL-1Ra for efficacy in monosodium urate (MSU) crystal-induced peritonitis. 5 days post-administration, PAS800–IL-1Ra significantly reduced leukocyte influx and inflammatory markers in MSU-induced peritonitis, whereas equimolar anakinra administered 24 h before MSU challenge was ineffective. The 6-h pretreatment with equimolar anakinra or PAS800–IL-1Ra before MSU challenge similarly reduced inflammatory markers. In cultured A549 lung carcinoma cells, anakinra, PAS600–IL-1Ra, and PAS800-IL-Ra reduced IL-1α–induced IL-6 and IL-8 levels with comparable potency. In human peripheral blood mononuclear cells, these molecules suppressed Candida albicans–induced production of the cancer-promoting cytokine IL-22. Surface plasmon resonance analyses revealed significant binding between PAS–IL-1Ra and IL-1R1, although with a slightly lower affinity than anakinra. These results validate PAS–IL-1Ra as an active IL-1 antagonist with marked in vivo potency and a significantly extended half-life compared with anakinra.

scholarly journals miR-125a-5p attenuates macrophage-mediated vascular dysfunction by targeting Ninjurin1

2022 ◽  
Author(s):  
Su Jung Hwang ◽  
Bum Ju Ahn ◽  
Min-Wook Shin ◽  
Ye-Seul Song ◽  
Youngbin Choi ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Inflammatory Diseases ◽  
Vascular Dysfunction ◽  
Expression Patterns ◽  
Cell Formation ◽  
Inhibitory Effect ◽  
Vascular Network ◽  
Inflammatory Factors ◽  
Vascular Integrity

AbstractNinjurin1 (Ninj1), an adhesion molecule, regulates macrophage function in hyaloid regression, multiple sclerosis, and atherosclerosis. However, its biological relevance and the mechanism underlying its function in vascular network integrity have not been studied. In this study, we investigated the role of Ninj1 in physiological (postnatal vessel formation) and pathological (endotoxin-mediated inflammation and diabetes) conditions and developed a strategy to regulate Ninj1 using specific micro (mi)RNAs under pathological conditions. Ninj1-deficient mice exhibited decreased hyaloid regression, tip cell formation, retinal vascularized area, recruitment of macrophages, and endothelial apoptosis during postnatal development, resulting in delayed formation of the vascular network. Five putative miRNAs targeting Ninj1 were selected using the miRanda algorithm and comparison of expression patterns. Among them, miR-125a-5p showed a profound inhibitory effect on Ninj1 expression, and miR-125a-5p mimic suppressed the cell-to-cell and cell-to-matrix adhesion of macrophages and expression of pro-inflammatory factors mediated by Ninj1. Furthermore, miR-125a-5p mimic inhibited the recruitment of macrophages into inflamed retinas in endotoxin-induced inflammation and streptozotocin-induced diabetes in vivo. In particular, miR-125a-5p mimic significantly attenuated vascular leakage in diabetic retinopathy. Taken together, these findings suggest that Ninj1 plays a pivotal role in macrophage-mediated vascular integrity and that miR-125a-5p acts as a novel regulator of Ninj1 in the management of inflammatory diseases and diabetic retinopathy.

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