Alternatively activated macrophages engage in homotypic and heterotypic interactions through IL-4 and polyamine-induced E-cadherin/catenin complexes

Bossche, Jan Van den; Bogaert, Pieter; Hengel, Jolanda van; Guérin, Christopher J.; Berx, Geert; Movahedi, Kiavash; Bergh, Rafaël Van den; Pereira-Fernandes, Anna; Geuns, Jan; Pircher, Hanspeter; Dorny, Pierre; Grooten, Johan; Baetseĺier, Patrick De; Ginderachter, Jo A. Van

doi:10.1182/blood-2009-05-221598

Cited by 105 publications

(117 citation statements)

References 46 publications

(66 reference statements)

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“…In this context, IL-4 stimulates the JAK/STAT pathway (JAK1/JAK3 and STAT6), leading to induction of E-cadherin/␤-catenin. 9,13 Moreover, previous studies and results of the present study demonstrate that IL-4 regulates expression of numerous molecules including MCP-1, IL-10, MMP-9, and TNF-␣ via unknown pathways. 10 -12,42-44 Thus, in addition to IL-4 -induced signals, it is appreciated that signals from the engagement of CCR2, TNFR1, and perhaps other receptors would integrate into multiple pathways.…”

Section: Discussionsupporting

confidence: 51%

“…28 Moreover, a recent study has linked E-cadherin induction with alternative activation and assumption of an epithelial-like phenotype by macrophages before fusion. 13 Thus, it is tempting to speculate that macrophages undergo alternative activation in the foreign body response. However, the concept of macrophage activation has expanded based on the theory that macrophages can exhibit overlapping gradients of activation including classical, alternative, and immunoregulatory activation.…”

Section: Discussionmentioning

confidence: 99%

“…9,10,13 To further characterize the participation of E-cadherin in fusion, its expression and distribution were detected by Western blot analysis and immunocytochemical analysis of bone marrow-derived macrophages, respectively. Both WT and MCP-1-null macrophages treated with IL-4 exhibited induction of Ecadherin at 24 and 48 hours, and both expressed more at 48 hours ( Figure 4G).…”

Section: Mcp-1-null Macrophages Exhibit Irregular Deposition Of E-cadmentioning

confidence: 99%

“…23,24 Moreover, E-cadherin association with ␤-catenin during IL-4 -induced macrophage fusion has been demonstrated. 13 It was wondered whether expression and distribution of ␤-catenin in WT and MCP-1-null macrophages mirrored that of E-cadherin. Examination of ␤-catenin levels by Western blot analysis revealed that it was induced similarly in WT and MCP-1-null macrophages and with a temporal pattern similar to that of E-cadherin ( Figure 4H).…”

Section: And B) At 72 Hours E-cadherin Distribution In Wt Cellsmentioning

confidence: 99%

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Lack of TNF-α–Induced MMP-9 Production and Abnormal E-Cadherin Redistribution Associated with Compromised Fusion in MCP-1–Null Macrophages

Skokos

Charokopos

Khan

et al. 2011

The American Journal of Pathology

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Homotypic cell fusion occurs in several cell types including macrophages in the formation of foreign body giant cells. Previously, monocyte chemoattractant protein-1 (MCP-1) was demonstrated to be required for foreign body giant cell formation in the foreign body response. The present study investigated the fusion defect in MCP-1-null macrophages by implanting biomaterials intraperitoneally in wildtype and MCP-1-null mice and monitoring the macrophage response at 12 hours to 4 weeks. MCP-1-null mice exhibited reduced accumulation and fusion of macrophages on implants, which was associated with attenuation of the foreign body response. Consistent with previous in vitro findings, the level of matrix metalloproteinase-9 (MMP-9) was reduced in MCP-1-null macrophages adherent to implants. In contrast, CCR2 expression was unaffected. In vitro studies revealed reduced tumor necrosis factor-␣ (TNF-␣) production and abnormal subcellular redistribution of E-cadherin and ␤-catenin during fusion in MCP-1-null macrophages. Exogenous TNF-␣ caused an increase in the production of MMP-9 and rescued the fusion defect. Addition of GM6001 (MMP inhibitor) or NSC23766 (Rac1 inhibitor) indicated two distinct induction pathways, one for E-cadherin/␤-catenin and one for MCP-1, TNF-␣, and MMP-9. Considered together, these observations demonstrate that induction of E-cadherin/␤-catenin is not sufficient for fusion in the absence of MCP-1 or the downstream mediators TNF-␣ and MMP-9. Moreover, attenuation of the foreign body response in intraperitoneal implants in MCP-1-null mice demonstrates that the process depends on tissue-specific factors.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Mcp-1-null Macrophages Exhibit Irregular Deposition Of E-cadmentioning

confidence: 99%

Section: And B) At 72 Hours E-cadherin Distribution In Wt Cellsmentioning

confidence: 99%

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Lack of TNF-α–Induced MMP-9 Production and Abnormal E-Cadherin Redistribution Associated with Compromised Fusion in MCP-1–Null Macrophages

Skokos

Charokopos

Khan

et al. 2011

The American Journal of Pathology

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“…Currently, the physiological function of CCL18 is thought to affect mainly chemotaxis and homing of leucocytes and the regulation of immunological response [22]. However, recent results of our group and others demonstrate that CCL18 is also involved in the induction of matrix production by fibroblasts [23,24]. Thus, CCL18 might also be engaged in the formation of the tumor stroma.…”

Section: Discussionmentioning

confidence: 89%

Serum Level of CC-Chemokine Ligand 18 is Increased in Patients with Non-small-cell Lung Cancer and Correlates with Survival Time in Adenocarcinomas

et al. 2012

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CC-chemokine ligand18 (CCL18) ismainly expressed by alternativelyactivated macrophages and DCs and plays an important role in lung fibrosis, arthritis and other diseases. Here CCL18 was measured in sera of 31 healthy volunteers and 170 patients with lung cancer and correlatedthese data with histology, tumor stage and clinicalparameters. Mean CCL18 serum levelofthe patients with non-small-cell lung cancer was 150(857) ng/ml vs. 32(61) ng/ml in the healthy control group. Patient groups differ significantly according their histology (adenocarcinoma 143(528) ng/ml vssquamous cell carcinoma 187(857) ng/ml, p,0.02). In addition, we found a significant difference between patients with lower versus higher T-stage (p,0.003). Receiver operating characteristic (ROC) analyses revealed a cutoff point of 83 ng/ml (area under the curve (AUC): 0.968; p,0.0001) to discriminate between healthy controls and non-small-cell lung cancer patients. ROC analyses to discriminate between patients, who died because of cancer related death and those who died for other reasons did not lead to a valid AUC. To stratify the tumor patients, a criterion value plot was performed leading to a point of equal sensitivity and specificity (54%) of 162 ng/ml. Patients with a CCL18 serum level higher than 160 ng/ml had a mean survival time of 623 days. In contrast, those in patients with a baseline level between 83 ng/ml and 160 ng/ml the mean survival time was 984 days (p,0.005). Survival-analysis revealed in adenocarcinoma a mean survival of 1152 days in the group below 83 ng/ml. In the median group the mean survival time was 788 days and in the group with the highest levels the mean survival time was 388 days (p,0.001). In contrast, we found no correlation between the FEV1 and the CCL18 baseline level. In conclusion, in patients suffering from adenocarcinoma increased serum CCL18 levels predict a diminished survival time.

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Metastasis

2012

Cancer as a Metabolic Disease

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Alternatively activated macrophages engage in homotypic and heterotypic interactions through IL-4 and polyamine-induced E-cadherin/catenin complexes

Cited by 105 publications

References 46 publications

Lack of TNF-α–Induced MMP-9 Production and Abnormal E-Cadherin Redistribution Associated with Compromised Fusion in MCP-1–Null Macrophages

Lack of TNF-α–Induced MMP-9 Production and Abnormal E-Cadherin Redistribution Associated with Compromised Fusion in MCP-1–Null Macrophages

Serum Level of CC-Chemokine Ligand 18 is Increased in Patients with Non-small-cell Lung Cancer and Correlates with Survival Time in Adenocarcinomas

Metastasis

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