Eosinophil chemokines

Zimmerman N, Hogan SP, Mishra A, Brandt EB, Bodette TR, Pope SM, Finkebnan FD, Rothenberg ME. Murine eotaxin-2 a constitutive eosinophil chemokine induced by allergen challenge and IL-4 overexpression. J Immunol 2000 165 5839-5846. 

Sabroe 1, A Hartnell, LA Jopling, S Bel, PD Ponath, JE Pease, PD Collins, TJ WUhams. 1999. Differential regulation of eosinophil chemokine signaling via CCR3 and non-CCR3 pathways. J Inununol 162 2946. 

Phillips, R., Stubbs, V.E.L.S., Henson, M.R., Williams. T.J., Pease, J.E., and Sabroe, I. (2003) Variations in eosinophil chemokine responses an investigation of CCRl and CCR3 fimction, expression in atopy, and identification of a functional CCRl promoter. Journal of Immunology (Baltimore, Md 1950), 170, 6190-6201. 

Zimmermann, N., Hogan, S.P., Mishra, A., Brandt, E.B., Bodette, T.R. et al. (2000) Murine eotaxin-2 A constitutive eosinophil chemokine induced by allergen challenge and lL-4 overexpression. Journal of Immunology (Baltimore, Md 1950), 165, 5839-5846. 

Frequently, the EAR is followed by a late phase response 4-6 h later and it is caused by the pulmonary sequestration of eosinophils, neutrophils, mast cells, and T-lymphocytes. This leukocyte recruitment depends on mast cell-derived mediators such as TNFa and various chemokines, as well as on the expression of adhesion molecules on leukocytes (e.g. VLA-4, CD11/18) and vascular endothelial cells (e.g. VCAM-1, ICAM-1, E-selectin). Products of these leukocytes have several functions First, they cause the second phase of bron-choconstriction, mucus secretion, and airway swelling second, they cause tissue destruction third, they launch and entertain the chronic inflammation. 

Proteolytic cleavage may also activate the chemokine. For example, CCL14 naturally displays a very weak affinity for CCRl and is unable to bind to CCR3 and CCR5 but shows an increase in CCRl affinity and gain of CCR3 and CCR5 affinity associated with chemotactic activity on lymphoblasts, monocytes, and eosinophils upon... 

Fig.l. Expression of CC and CXC chemokine receptors by inflammatory and structural cells in allergic lung disease. Eos, eosinophil Mac, macrophage Mono, monocyte. 

Chensue SW, Lukacs NW, Yang TY, et al. Aberrant in vivo T helper type 2 cell response and impaired eosinophil recruitment in CC chemokine receptor 8 knockout mice. J Exp Med 2001 193(5) 573-584. 

Liu LY, Jarjour NN, Busse WW, Kelly EA. Chemokine receptor expression on human eosinophils from peripheral blood and bronchoalveolar lavage fluid after segmental antigen challenge. J Allergy Clin Immunol 2003 112(3) 556-562. 

Sabroe I, Peck MJ, Van Keulen BJ, et al. A small molecule antagonist of chemokine receptors CCR1 and CCR3. Potent inhibition of eosinophil function and CCR3-mediated HIV-1 entry. J Biol Chem 2000 275(34) 25985-25992. 

White JR, Lee JM, Dede K, et al. Identification of potent, selective non-peptide CC chemokine receptor-3 antagonist that inhibits eotaxin-, eotaxin-2-, and monocyte chemotactic protein-4-induced eosinophil migration. J Biol Chem 2000 275(47) 36626-36631. 

Lukacs NW, Standiford TJ, Chensue SW, Kunkel RG, Stricter RM, Kunkel SL. C-C chemokine-induced eosinophil chemotaxis during allergic airway inflammation. J Leukoc Biol 1996 60(5) 573-578. 

Eisner J, Petering H, Hochstetter R, et al. The CC chemokine antagonist Met-RANTES inhibits eosinophil effector functions through the chemokine receptors CCR1 and CCR3. Eur J Immunol 1997 27(ll) 2892-2898. 

Nagase H, Kudo K, Izumi S, et al. Chemokine receptor expression profile of eosinophils at inflamed tissue sites decreased CCR3 and increased CXCR4 expression by lung eosinophils. J Allergy Clin Immunol 2001 108(4) 563-569. 

Persson T, Monsef N, Andersson P, et al. Expression of the neutrophil-activating CXC chemokine ENA-78/CXCL5 by human eosinophils. Clin Exp Allergy 2003 33(4) 531-537. 

Persson-Dajotoy T, Andersson P, Bjartell A, Calafat J, Egesten A. Expression and production of the CXC chemokine growth-related oncogene-alpha by human eosinophils. J Immunol 2003 170(10) 5309-5316. 

Struyf S, Proost P, Schols D, et al. CD26/dipeptidyl-peptidase IV down-regulates the eosinophil chemotactic potency, but not the anti-HIV activity of human eotaxin by affecting its interaction with CC chemokine receptor 3. J Immunol 1999 162 4903 1909. 

In sensitized asthmatic individuals, antigen challenge generally causes a Type I (IgE-mediated) immediate hypersensitivity response by release of preformed mediators, including histamine, and prostaglandins, which are responsible for bronchoconstric-tion and increased vascular permeability. Between 2 and 8 hours after the immediate response, asthmatics experience a more severe and prolonged (late phase) reaction that is characterized by mucus hyper-secretion, bronchoconstriction, airway hyperresponsiveness to a variety of nonspecific stimuli (e.g., histamine, methacholine), and airway inflammation characterized by eosinophils. This later response is driven by leukotrienes, chemokines and cytokines synthesized by activated mast cells and Th2 cells. Both proteins and haptens have been associated with these types of reactions. 

The effect of MAPK activation on cellular processes that affect cell function and the resulting pharmacology has been delineated using modem techniques such as knock-out cells and animals [1,3,6]. Activation of MAPK in inflammatory cells such as T-cells, B-cells, macrophages and eosinophils leads to expression and/or activation of pro-inflammatory genes and mediators such as interleukin-1(3 (IL-1(3), TNFa, IL-6, chemokines [e.g., IL-8, macrophage inflammatory factor-1 a, (3 (MIP-la,[3)J, MMPs and toxic molecules such as free radicals and nitric oxide [1,3]. These pro-inflammatory mediators induce cellular proliferation, differentiation, survival, apoptosis and tissue degradation/destruction and help induce chronic inflammation. Inhibition of any one or more of the MAPK family... 

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