Anti-Chemokine Therapy for Inflammatory Diseases

2007 ◽  
Vol 20 (3) ◽  
pp. 447-453 ◽  
Author(s):  
M.L. Castellani ◽  
K. Bhattacharya ◽  
M. Tagen ◽  
D. Kempuraj ◽  
A. Perrella ◽  
...  
Keyword(s):  
Chemokine Receptors ◽  
Inflammatory Diseases ◽  
Heart Diseases ◽  
Diagnostic Procedures ◽  
Inflammatory Cells ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Clinical Scenarios ◽  
Inflammatory Proteins ◽  
G Protein Coupled

Chemokines are inflammatory proteins acting via G-protein coupled chemokine receptors that trigger different signaling pathways. Monocyte chemoattractant protein-1 (CCL2/MCP-1) and regulated on activation, normal T expressed and secreted (CCL5/RANTES) are the two major members of the CC chemokine beta subfamily. The roles of RANTES and MCP-1 are emerging in regulating the recruitment of inflammatory cells into tissue during inflammation. The inhibition of MCP-1 and RANTES with corresponding antibodies or other inhibitors may provide benefits in different clinical scenarios including cancer, inflammation, CNS disorders, parasitic disease, autoimmune and heart diseases. RANTES and MCP-1 may represent targets for diagnostic procedures and therapeutic intervention, and may be useful as a prognostic factor in the above diseases.

scholarly journals Human Herpesvirus 6 Open Reading Frame U12 Encodes a Functional β-Chemokine Receptor

1998 ◽  
Vol 72 (7) ◽  
pp. 6104-6112 ◽  
Author(s):  
Yuji Isegawa ◽  
Zou Ping ◽  
Kazushi Nakano ◽  
Nakaba Sugimoto ◽  
Koichi Yamanishi
Keyword(s):  
Chemokine Receptors ◽  
Human Herpesvirus ◽  
Murine Cytomegalovirus ◽  
Human Herpesvirus 6 ◽  
Monocyte Chemoattractant Protein 1 ◽  
Reading Frame ◽  
Homologous Genes ◽  
Inflammatory Proteins ◽  
Herpesvirus 6

ABSTRACT Human herpesvirus 6 (HHV- 6), which belongs to the betaherpesvirus subfamily and infects mainly T cells in vitro, causes acute and latent infections. HHV- 6 contains two genes (U12 and U51) that encode putative homologs of cellular G-protein-coupled receptors (GCR), while three other betaherpesviruses, human cytomegalovirus, murine cytomegalovirus, and human herpesvirus 7, have three, one, and two GCR-homologous genes, respectively. The U12 gene is expressed late in infection from a spliced mRNA. The U12 gene was cloned, and the protein was expressed in cells and analyzed for its biological characteristics. U12 functionally encoded a calcium-mobilizing receptor for β-chemokines such as regulated upon activation, normal T expressed and secreted (RANTES), macrophage inflammatory proteins 1α and 1β (MIP-1α and MIP-1β) and monocyte chemoattractant protein 1 but not for the α-chemokine interleukin-8, suggesting that the chemokine selectivity of the U12 product was distinct from that of the known mammalian chemokine receptors. These findings suggested that the product of U12 may play an important role in the pathogenesis of HHV- 6 through transmembrane signaling by binding with β-chemokines.

scholarly journals Chronic inflammation upregulates chemokine receptors and induces neutrophil migration to monocyte chemoattractant protein-1

1999 ◽  
Vol 103 (9) ◽  
pp. 1269-1276 ◽  
Author(s):  
Brent Johnston ◽  
Alan R. Burns ◽  
Makoto Suematsu ◽  
Thomas B. Issekutz ◽  
Richard C. Woodman ◽  
...  
Keyword(s):  
Chronic Inflammation ◽  
Chemokine Receptors ◽  
Neutrophil Migration ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein

TRAF-1 Deficient Mice Show Impaired Monocyte Recruitment and Decreased Atherogenesis

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 696-696
Author(s):  
Anna Missiou ◽  
Natascha Köstlin ◽  
Christian Münkel ◽  
Dietmar Pfeifer ◽  
Katja Zirlik ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Chemokine Receptors ◽  
Inflammatory Diseases ◽  
Inflammatory Cells ◽  
Adaptor Proteins ◽  
High Cholesterol Diet ◽  
Cell Content ◽  
Monocyte Recruitment

Abstract Members of the tumor necrosis factor (TNF) interleukin/toll-like receptor superfamily such as CD40L, TNFa, and IL-1b potently promote atherogenesis in mice and likely also in humans. TNF receptor associated factors (TRAFs) are cytoplasmic adaptor proteins for this group of cytokines. We recently reported over-expression of TRAFs in murine and human atheromata and demonstrated dependency of classic inflammatory functions on TRAFs in endothelial cells and macrophages. Here we test the hypothesis that TRAF-1 modulates atherogenesis in vivo. TRAF-1--/LDLR--mice fed a high cholesterol diet for 18 weeks developed significantly smaller atherosclerotic lesions compared with LDLR--controls. Intimal lesion size decreased by up to 56±6% and 33±5% in sections of the aortic arch and aortic root, respectively (n>10 per group, P<0.01 each). Plaques of TRAF-1-deficient animals contained up to 46±9% and 55±4% fewer macrophages while smooth muscle cell content increased by up to 32±6 and 36±7%, characteristics associated with non disrupted plaques in humans. Lipid content, collagen content, and lymphocyte content remained unchanged. In vitro, gene expression profiling revealed reduced expression of adhesion molecules (VCAM-1, ICAM-1), chemokines (CCL2, CXCL2), and growth factors (M-CSF) in TRAF-1-deficient endothelial cells as well as of integrins (CD29, CD11b) and chemokines/chemokine receptors (CXCL2, CCR1) in TRAF-1-deficient macrophages, verified by siRNA studies in human cells. Finally, both deficiency of TRAF-1 in endothelial cells and neutrophils/monocytes reduced adhesion of inflammatory cells to the endothelium in static and dynamic adhesion assays. We present the novel finding that TRAF 1 deficiency attenuates atherogenesis in mice, an effect most likely mediated by impaired monocyte recruitment to the vessel wall. These data identify TRAF-1 as potential treatment target for chronic inflammatory diseases such as atherosclerosis.

A New Diterpene and Anti-inflammatory Sesquiterpene Lactones from Sigesbeckia orientalis

Planta Medica ◽  
2020 ◽  
Vol 86 (15) ◽  
pp. 1108-1117
Author(s):  
Nora S. Engels ◽  
Barbara Gierlikowska ◽  
Birgit Waltenberger ◽  
Fang-Rong Chang ◽  
Anna K. Kiss ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Sesquiterpene Lactones ◽  
Surface Expression ◽  
Interleukin 8 ◽  
Human Neutrophils ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Ic50 Values ◽  
Factor Α ◽  
Necrosis Factor

Abstract Sigesbeckia orientalis, more commonly referred to as Herba Sigesbeckiae or Xi Xian Cao in traditional Chinese medicine and hy thiêm in traditional Vietnamese medicine, is used in China and Vietnam to treat inflammatory diseases such as arthritis, rheumatism, and joint pain. In initial investigations, the dichloromethane extract from the aerial parts of S. orientalis showed distinct inhibitory effects on the release of interleukin-8 in human neutrophils. Therefore, the purpose of the present study was the phytochemical investigation of the bioactive dichloromethane extract and the in vitro analysis of the effects of the isolated compounds on interleukin-8, interleukin-1β, tumor necrosis factor-α, and monocyte chemoattractant protein 1 release, and surface expression of adhesion molecules (CD11a, CD11b, and CD62L) in lipopolysaccharide-stimulated human neutrophils to identify the active principle(s). The separation of the bioactive dichloromethane extract using various chromatographic techniques led to the isolation of nine compounds. Their chemical structures were elucidated from nuclear magnetic resonance and mass spectrometry data. One diterpene, 17(13 → 14)-abeo-ent-3S*,13S*,16-trihydroxystrob-8(15)-ene, was identified as a new natural product. Three germacranolide sesquiterpene lactones inhibited interleukin-8 production with IC50 values between 1.6 and 6.3 µM, respectively, and tumor necrosis factor-α production with IC50 values between 0.9 and 3.3 µM, respectively. Furthermore, they significantly inhibited interleukin-1β and monocyte chemoattractant protein 1 production and diminished the effects of lipopolysaccharide on the surface expression of the adhesion molecules CD11a, CD11b, and CD62L. These findings support the traditional use of S. orientalis in the treatment of inflammatory diseases.

scholarly journals Site-directed mutagenesis of monocyte chemoattractant protein-1 identifies two regions of the polypeptide essential for biological activity

1996 ◽  
Vol 313 (2) ◽  
pp. 633-640 ◽  
Author(s):  
Clifford J. BEALL ◽  
Sangeeta MAHAJAN ◽  
Donald E. KUHN ◽  
Pappachan E. KOLATTUKUDY
Keyword(s):  
Biological Activity ◽  
Inflammatory Diseases ◽  
Expression System ◽  
Point Mutations ◽  
Site Directed Mutagenesis ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
Monocyte Migration ◽  
Important Region

Monocyte chemoattractant protein-1 (MCP-1) mediates monocyte migration into tissues in inflammatory diseases and atherosclerosis. We have investigated structure-activity relationships for human MCP-1. Mutations were introduced based upon differences between MCP-1 and the structurally related but functionally distinct molecule interleukin-8 (IL-8). Mutant proteins produced using the baculovirus/insect cell expression system were purified and their ability to stimulate monocyte chemotaxis and elevation of intracellular calcium in THP-1 monocytic leukaemia cells was measured. Two regions in MCP-1 were identified as important for its biological activity. One region consists of the sequence Thr-Cys-Cys-Tyr (amino acids 10-13). Point mutations of Thr-10 to Arg and Tyr-13 to Ile greatly lowered MCP-1 activity. The second functionally important region is formed by Ser-34 and Lys-35. Insertion of a Pro between these two residues, or their substitution by the sequence Gly-Pro-His, caused nearly complete loss of MCP-1 activity. Competition binding experiments showed that the mutations that affected activity also lowered the ability to compete with wild-type MCP-1 for receptors on THP-1 cells. Point mutations at positions 8, 15, 30, 37, 38 and 68 had little effect on MCP-1 activity. The important regions that we have identified in MCP-1 correspond with previously identified functionally important regions of IL-8, suggesting that the two molecules bind to their respective receptors by similar contacts.

scholarly journals Renal expression of monocyte chemoattractant protein-1 in lupus autoimmune mice.

1997 ◽  
Vol 8 (5) ◽  
pp. 720-729 ◽  
Author(s):  
C Zoja ◽  
X H Liu ◽  
R Donadelli ◽  
M Abbate ◽  
D Testa ◽  
...  
Keyword(s):  
New Zealand ◽  
Lupus Nephritis ◽  
Mononuclear Cell ◽  
Blot Analysis ◽  
Inflammatory Cells ◽  
Mononuclear Cell Infiltration ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
Old Mice

Mononuclear cell infiltration in glomeruli and renal interstitium is a prominent feature of some types of glomerulonephritis, including lupus nephritis. The mechanism(s) underlying monocyte influx into the kidney is not fully understood. Recently, monocyte chemoattractant protein-1 (MCP-1) has been identified as a chemotactic factor involved in the recruitment of monocytes/macrophages in the glomeruli of rats with mesangioproliferative as well as anti-glomerular basement membrane glomerulonephritis. In the study presented here, renal MCP-1 mRNA expression in New Zealand Black x New Zealand White (NZB/W) F1 mice, a model of genetically determined immune complex disease that mimics systemic lupus in humans, was investigated. Northern blot analysis revealed a single 0.7 kb MCP-1 transcript of very low intensity in kidneys from 2-month-old NZB/W mice that had not yet developed proteinuria nor renal damage. Message levels, which increased markedly with the progression of nephritis and in association with mononuclear cell infiltration, were 10- and 15- fold higher in 8-10-month-old mice than in 2-month-old mice. By in situ hybridization, increased expression of MCP-1 mRNA was demonstrated in glomeruli and, even more striking, in tubular epithelial cells. Western blot analysis demonstrated increased expression of MCP-1 protein in kidneys of 10-month-old NZB/W mice, consistent with MCP-1 mRNA data. When NZB/W mice were treated with cyclophosphamide up to 12 months of age, expression of MCP-1 in the renal tissue remained low, the influx of inflammatory cells did not appear, and glomerular and tubular structures remained well preserved. These data suggest that elevated MCP-1 might act as a signal for inflammatory cells to infiltrate the kidney in lupus nephritis.

Neutrophilic dermatoses

2013 ◽  
pp. 1426-1433
Author(s):  
Pia Moinzadeh ◽  
Thomas Krieg
Keyword(s):  
Skin Diseases ◽  
Inflammatory Diseases ◽  
Diagnostic Procedures ◽  
Inflammatory Cells ◽  
Skin Lesions ◽  
Cutaneous Lesions ◽  
Neutrophilic Dermatoses ◽  
Systemic Symptoms ◽  
Dermal Infiltrate ◽  
Exanthematous Pustulosis

Neutrophilic dermatoses (ND) comprise a heterogeneous group of non-infectious skin diseases characterized by a diffuse epidermal and/or dermal infiltrate consisting of polymorphonuclear neutrophilic inflammatory cells throughout the different skin layers. Depending on the localization of this infiltrate, patients may present with a variety of skin lesions such as pustules/vesiculopustules (epidermal infiltrate), plaques or papules (dermal infiltration), nodules or ulcerations (deep dermal/subcutaneous infiltrate) and also with possible systemic symptoms, such as leucocytosis, arthralgias, myalgia, and malaise. Based on the clinical picture of cutaneous lesions and further systemic symptoms the patients can be subdivided into different entities. These include Sweet’s syndrome (SS), pyoderma gangrenosum (PG), rheumatoid neutrophilic dermatitis, bowel-associated dermatosis-arthritis syndrome, subcorneal pustular dermatosis (Sneddon Wilkinson), acute generalized exanthematous pustulosis (AGEP), acrodermatitis continua of Hallopeau (ACH), palmoplantare pustuloses (PPP), pustular bacterid (PB), neutrophilic eccrine hidradenitis, and Behçet’s disease. The pathogenesis is still not fully elucidated but it has been hypothesized that it is associated with immunological dysfunctions, with abnormal cytokine signalling, causing an uncontrolled recruitment of neutrophilic cells. ND can be triggered by underlying systemic inflammatory diseases, malignancies, haematological disorders and/or medication use. Diagnostic procedures include detailed physical examination, laboratory tests, and histopathological assessments. The therapeutic management of ND is mainly based on systemic steroids in acute cases and immunosuppressive or immunomodulatory drugs in chronic forms. Underlying systemic conditions have to be diagnosed and treated as early as possible to avoid complications.

Interleukin-8 and monocyte chemoattractant protein-1 mRNAs in oxygen-injured rabbit lung

1995 ◽  
Vol 268 (5) ◽  
pp. L826-L831 ◽  
Author(s):  
C. T. D'Angio ◽  
R. A. Sinkin ◽  
M. B. LoMonaco ◽  
J. N. Finkelstein
Keyword(s):  
Mrna Expression ◽  
Inflammatory Cells ◽  
Interleukin 8 ◽  
Polymorphonuclear Cells ◽  
Rabbit Lung ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
Oxygen Exposure ◽  
Pulmonary Response

The chemokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) are neutrophil and monocyte attractants, respectively. We hypothesized that IL-8 and MCP-1 mRNA expression in alveolar macrophages (AM) lavaged from rabbit lung would be increased by oxygen exposure, which is known to induce inflammation. Adult rabbits were exposed to > 95% oxygen for up to 64 h and allowed to recover in room air for up to 72 h before killing and pulmonary lavage. Numbers of lavageable polymorphonuclear cells (PMN) and AM rose during the exposure protocol. Quantitative in situ hybridization with 3H-labeled cRNA probes showed both IL-8 and MCP-1 mRNA expression in AM during oxygen exposure, with peak levels of IL-8 mRNA at 56-h oxygen exposure and of MCP-1 mRNA at 64-h oxygen exposure with 24-h room air recovery. IL-8 mRNA was present in PMN between 48-h oxygen exposure and 64-h oxygen exposure with 24-h room air recovery. MCP-1 mRNA was not expressed in PMN. This pattern of chemokine mRNA expression emphasizes the importance of inflammatory cells as effectors in the pulmonary response to oxygen exposure.

scholarly journals RANTES and Monocyte Chemoattractant Protein–1 (MCP-1) Play an Important Role in the Inflammatory Phase of Crescentic Nephritis, but Only MCP-1 Is Involved in Crescent Formation and Interstitial Fibrosis

1997 ◽  
Vol 185 (7) ◽  
pp. 1371-1380 ◽  
Author(s):  
Clare M. Lloyd ◽  
Andrew W. Minto ◽  
Martin E. Dorf ◽  
Amanda Proudfoot ◽  
Timothy N.C. Wells ◽  
...  
Keyword(s):  
Functional Role ◽  
Type I Collagen ◽  
Interstitial Fibrosis ◽  
Inflammatory Cells ◽  
Type I ◽  
Crescent Formation ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
Inflammatory Phase

The involvement of chemokines in inflammation is well established, but their functional role in disease progression, and particularly in the development of fibrosis, is not yet understood. To investigate the functional role that the chemokines monocyte chemoattractant protein–1 (MCP-1) and RANTES play in inflammation and the progression to fibrosis during crescentic nephritis we have developed and characterized a murine model for this syndrome. Significant increases in T-lymphocytes and macrophages were observed within glomeruli and interstitium, paralleled by an induction of mRNA expression of MCP-1 and RANTES, early after disease initiation. Blocking the function of MCP-1 or RANTES resulted in significant decreases in proteinuria as well as in numbers of infiltrating leukocytes, indicating that both MCP-1 and RANTES (regulated upon activation in normal T cells expressed and secreted) play an important role in the inflammatory phase of crescentic nephritis. In addition, neutralization of MCP-1 resulted in a dramatic decrease in both glomerular crescent formation and deposition of type I collagen. These results highlight a novel role for MCP-1 in crescent formation and development of interstitial fibrosis, and indicate that in addition to recruiting inflammatory cells this chemokine is critically involved in irreversible tissue damage.

Sign in / Sign up

Export Citation Format

Share Document