Disease relevance of Ccl11

• The identification of constitutive eotaxin mRNA expression in multiple tissues suggests that in addition to regulating airway eosinophilia, eotaxin is likely to be involved in eosinophil recruitment into other tissues as well as in baseline tissue homing [1].
• Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production [2].
• Treatment of cpdm/cpdm mice with CCL11-neutralizing polyclonal antibodies did not affect the number of eosinophils in the skin or the severity of the dermatitis [3].
• Such mice demonstrate that eotaxin enhances the magnitude of the early (but not late) eosinophil recruitment after antigen challenge in models of asthma and stromal keratitis [4].
• Expression and participation of eotaxin during mycobacterial (type 1) and schistosomal (type 2) antigen-elicited granuloma formation [5].

High impact information on Ccl11

• Mouse Eotaxin expression parallels eosinophil accumulation during lung allergic inflammation but it is not restricted to a Th2-type response [6].
• We describe the identification and cloning of a cDNA that encodes a mouse C-C chemokine with 68% amino acid identity to guinea pig Eotaxin [6].
• The mRNA expression of mouse Eotaxin is not restricted to Th2 T cells in vitro and is independent of the development of a Th2-type response during N. brasiliensis infection, in vivo [6].
• Notably, in mice deficient in IL-5/eotaxin the ability of CD4(+) T helper cell (Th)2 lymphocytes to produce IL-13, a critical regulator of airways smooth muscle constriction and obstruction, was significantly impaired [7].
• Neutralization of RANTES (regulated upon activation, normal T cell expressed and secreted) receptor(s) with a receptor antagonist decreases significantly lymphocyte and eosinophil infiltration as well as mRNA expression of eotaxin and RANTES [8].

Chemical compound and disease context of Ccl11

• The eotaxin chemokines and CCR3 are fundamental regulators of allergen-induced pulmonary eosinophilia [9].
• Finally, the intestinal eosinophilia induced by the eotaxin transgene was beta(7) integrin-dependent [10].
• Dexamethasone reduced airway eosinophilia, AHR, and protein and mRNA for eotaxin and IL-5 [11].
• CONCLUSION: Selective components of the IL-13-induced asthma phenotype--airway eosinophilia but not mucus secretion--are differentially regulated by IL-5 and eotaxin [12].
• Piclamilast treatment dose-dependently and significantly prevented the increase in inflammatory cell number and goblet cell hyperplasia, as well as production of cytokines, including eotaxin, TNFalpha and IL-4 [13].

Biological context of Ccl11

• Using a guinea pig lung cDNA library, we have cloned full-length eotaxin cDNA [1].
• Taken together, these results suggest that CD8(+) cells from sensitized SD rats exhibit the functional capacity to suppress the LAR, possibly through downregulation of eotaxin expression and increased expression of IFN-gamma mRNA [14].
• CONCLUSIONS: Acute rejection of corneal xenografts in mice is mediated by T cells that display a mixed T-helper (Th) type 2/Th1 phenotype and secrete eotaxin, an eosinophil chemoattractant [15].
• In contrast, the mutants K26 (amino-terminus) E179 and E180 (ECL2) responded in chemotaxis assays to CCL11 and CCL24, but not to CCL26 [16].
• Functional responsiveness to eotaxin was increased in IL5TG eosinophils as demonstrated by a 10x increase in its potency in producing actin polymerization and 3x increase in CD11b upregulation relative to WT [17].

Anatomical context of Ccl11

• Consistent with its putative role in eosinophilic inflammation, eotaxin induces the selective infiltration of eosinophils when injected into the lung and skin [1].
• High constitutive levels of eotaxin mRNA expression were observed in the lung, while the intestines, stomach, spleen, liver, heart, thymus, testes, and kidney expressed lower levels [1].
• These latter effects would appear to be selective because no changes were observed when macrophage-inflammatory protein-1alpha, eotaxin, or MCP-3 were instilled into the airways of normal mice or when mast cells were treated in vitro [18].
• Correlating with the decreased cellular infiltration, delta chain T-cell receptor-deficient (TCR delta(-/-)) mice exhibited substantially reduced levels of most of the chemokines analyzed (with the exception of eotaxin) [19].
• We challenged wild-type (WT) BALB/c, CCL11 single knockout (SKO) and CCL11 IL-5 double knockout (DKO) mice with either T. spiralis muscle larvae or T. muris eggs in order to examine eosinophil recruitment to the small and large intestine during helminth infection [20].

Associations of Ccl11 with chemical compounds

• Thus, eotaxin mRNA levels are increased in response to allergen challenge during the late phase response [1].
• To investigate further contribution of CC chemokines, we administered a 35-kD CC chemokine neutralizing protein (vCKBP) in vivo. vCKBP inhibited the eosinophil accumulation induced by eotaxin and ovalbumin, but did not block that induced by LPS or LPW [21].
• Alanine scanning mutagenesis of the chemokine receptor CCR3 reveals distinct extracellular residues involved in recognition of the eotaxin family of chemokines [16].
• Taken together, these results demonstrate that expression of eotaxin and IL-5 in intestinal epithelium induces compartmentalized dysregulation of eosinophil trafficking and the important role of the beta(7) integrin in gastrointestinal allergic responses [10].
• In addition, equivalent numbers of dispersed lung cells from L-NAME- and aminoguanidine-treated mice produced significantly higher levels of IL-4, monocyte chemoattractant protein (MCP)-1, and macrophage inflammatory protein (MIP)-1alpha and significantly lower levels of eotaxin compared with D-NAME-treated mice [22].

Physical interactions of Ccl11

• Furthermore, transgenic mice expressing eotaxin in the intestine (with the rat fatty acid-binding promoter) were used to specifically elucidate the contribution of this chemokine in eosinophil-associated gastrointestinal disease-associated bronchial hyperresponsiveness [23].

Regulatory relationships of Ccl11

• Neither IL-4 nor eotaxin were significantly induced in Stat6(-/-) mice after infection with N. brasiliensis [24].
• Functional effects of eotaxin are selectively upregulated on IL-5 transgenic mouse eosinophils [17].
• Eotaxin is also induced locally in response to the transplantation of interleukin 4-secreting tumor cells, indicating that it likely contributes to the eosinophil recruitment and antitumor effect of interleukin 4 [25].
• The eotaxin gene is widely (but not ubiquitously) expressed in normal mice and is strongly induced in cultured endothelial cells in response to interferon gamma [25].
• Interestingly, IL-13-induced eosinophilia in the bronchoalveolar lavage fluid of eotaxin-deficient mice was not impaired; however, these same mice failed to mount a significant tissue eosinophilia in response to IL-13 [12].

Other interactions of Ccl11

• Moreover, IL-5 was found to be an eosinophil chemotactic factor by the checkerboard assay [26].
• The adhesion molecule VCAM-1 and eotaxin have been implicated in extravasation and accumulation of eosinophils into tissue in animal models of asthma [27].
• However, these cells were neither the main producers of the major eosinophilic chemokines eotaxin, RANTES, or MIP-1alpha, nor did they regulate the expression of these chemokines [28].
• Unexpectedly, expression of only three chemokines, CCL11, CCL17, and CCL22, was STAT6 dependent, and many of the identified chemokines were overexpressed in STAT6-deficient mice, providing an explanation for the enhanced neutrophilic inflammation seen in these mice [29].
• Messages encoding eotaxin, macrophage inflammatory protein (MIP)-1alpha, and MIP-2 were elevated after 4 and 24 h of exposure to 1 ppm ozone [30].

Analytical, diagnostic and therapeutic context of Ccl11

• Eotaxin was overexpressed in eyes with rejected corneal xenografts [15].
• The concentration of CCL11 protein was increased two- to threefold in the skin of cpdm/cpdm mice by enzyme-linked immunosorbent assay [3].
• Eotaxin was monitored by protein ELISA and semiquantitative reverse-transcriptase PCR mRNA analysis [5].
• Both pranlukast and SB210661 significantly attenuated BHR induced by eotaxin with logPC(50), which is the concentration of acetylcholine needed to increase baseline insufflation pressure by 50%, from -0.43 +/- 0.16 to 0.39 +/- 0.10 and from -0.22 +/- 0.10 to 0.53 +/- 0.10, respectively (p < 0.05) [31].
• Finally, eotaxin and VACM-1 expression in the lung was assessed by immunohistochemistry [32].

References