Upregulation Of CCL11 Research Articles

Combined adjuvant effects of ambient vapor-phase organic components and particulate matter potently promote allergic sensitization and Th2-skewing cytokine and chemokine milieux in mice: The importance of mechanistic multi-pollutant research

Although exposure to ambient particulate matter (PM) is linked to asthma, the health effects of co-existing vapor-phase organic pollutants (vapor) and their combined effects with PM on this disease are poorly understood. We used a murine asthma model to test the hypothesis that exposure to vapor would enhance allergic sensitization and this effect would be further strengthened by co-existing PM. We found that vapor and PM each individually exerted adjuvant effects on OVA sensitization. Co-exposure to vapor and PM during sensitization further enhanced allergic lung inflammation and OVA-specific antibody production which was accompanied by pulmonary cytokine/chemokine milieu that favored T-helper 2 immunity (i.e. increased IL-4, downregulation of Il12a and Ifng, and upregulation of Ccl11 and Ccl8). TNFα, IL-6, Ccl12, Cxcl1 and detoxification/antioxidant enzyme responses in the lung were pollutant-dependent. Inhibition of lipopolysaccharide-induced IL-12 secretion from primary antigen-presenting dendritic cells correlated positively with vapor’s oxidant potential. In conclusion, concurrent exposure to vapor and PM led to significantly exaggerated adjuvant effects on allergic lung inflammation which were more potent than that of each pollutant type alone. These findings suggest that the effects of multi-component air pollution on asthma may be significantly underestimated if research only focuses on a single air pollutant (e.g., PM).

Abstract 5942: An integrated approach reveals novel extrinsic pathways and cytokine signatures associated with drug response in acute myeloid leukemia

Abstract Background: Acute myeloid leukemia (AML) is a heterogeneous disease with a dismal 5 year survival rate below 30%. Current AML therapies have provided little improvement in achieving complete remission. This is attributed to the development of drug resistance and extrinsic factors from the microenvironment that promote AML progression. Previously, our lab demonstrated that proinflammatory cytokines from the bone marrow microenvironment such as IL-1, promote AML progression. This emphasizes the rationale to design and implement targeted therapies to block extrinsic pathways coupled with intrinsic pathways conferring drug resistance in AML. Methods: To identify factors that promote drug sensitivity and resistance in AML, we used a cohort of 350 AML patients with various genetic subtypes. We quantified levels of 41 growth factors in plasma samples using a multiplex luminex assay. The same cohort of AML samples were analyzed for drug response to 130 small molecule inhibitors in in vitro functional drug sensitivity assay, for RNA-seq gene expression, and whole exome sequencing. The data was integrated to identify differential pathways and markers for drug response. To model drug response in vitro we created a series of drug resistant AML cell lines by culturing these cells in specific drugs long-term. Results: Pathway analysis integrating drug sensitivity, transcriptome, and cytokine expression data identified distinct differentially regulated pathways for various inhibitors. We found that protein synthesis pathways were significantly enriched in sorafenib (FLT-3 inhibitor) resistant samples whereas cytokine and immune pathways (such as TLR and MCP1 signaling) were correlated with trametinib (MEK inhibitor) and venetoclax (Bcl-2 inhibitor) resistance. Specifically, venetoclax resistance correlated with augmented levels of cytokines such as IL-1 and IP-10 and growth factors such as PDGF. Further, trametinib resistance in AML samples is correlated with the upregulation of CCL11, MCP1, and TGFα but a downregulation of CCL22 levels. Accordingly, using AML cell line models, we observed an increase in MCP1 and TGFα at the transcript and secreted protein levels in trametinib resistant cell lines. We demonstrated that MCP1 stimulation activates survival pathways by activating pERK and pJNK signaling, thus reducing apoptosis in AML cells. Targeting MCP1 in combination with trametinib reverses these effects, thus offering a novel therapeutic approach to overcome drug resistance. Conclusion and perspectives: Our data suggest that distinct extrinsic pathways may regulate the response to specific targeted therapy, thus providing a strong basis to design new treatment regimens. Combination treatment incorporating extrinsic pathways would aid in sensitizing AML cells to therapy. Our study offers an integrated approach and a resource to identify such pathways for a large number of tested drugs, and narrows down functionally important pathways associated with drug response. Citation Format: Rucha V. Modak, Alisa Damnernsawad, Ted Laderas, Guanming Wu, Jeffery W. Tyner, Karin D. Rodland, Shannon K. McWeeney, Anupriya Agarwal. An integrated approach reveals novel extrinsic pathways and cytokine signatures associated with drug response in acute myeloid leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5942.

S-allyl cysteine ameliorates cyclophosphamide-induced downregulation of urothelial uroplakin IIIa with a concomitant effect on expression and release of CCL11and TNF-α in mice.

The aim of this study was to evaluate the modulatory effect of S-allyl cysteine against cyclophosphamide-induced changes in uroplakin IIIa, CCL11 and TNF-α. Mice were treated with cyclophosphamide (200mg/kg×7 d, ip). S-allyl cysteine (150mg/kg×7d, ip), and comparator compound mesna (40mg/kg×7d, ip) were administered 1h before and 4h after each cyclophosphamide dose. The urinary bladder was analysed for mRNA and protein changes in uroplakin IIIa (UPIIIa), CCL11 and TNF-α and histopathological findings. Cyclophosphamide caused hemorrhagic cystitis formation and downregulation of UPIIIa. These changes were accompanied by upregulation of CCL11 and TNF-α. S-allyl cysteine attenuated these changes including protection at histological level. Mesna which was used as a comparator drug also showed protection. However, relatively S-allyl cysteine showed a stronger protective effect than mesna. These findings highlight a correlation between downregulaion of UPIIIa and enhanced production of inflammatory biomarkers and protective effects of S-allyl cysteine which has been reported to be a potent uroprotective agent. The present study strengthens its role which could be clinically exploited in chemotherapy regimen.

Up-regulation of CCL11 and CCL26 is associated with activated eosinophils in bullous pemphigoid

Eosinophils contribute to the pathogenesis of bullous pemphigoid (BP) by secretion of proinflammatory cytokines and proteases. Trafficking of eosinophils into tissue in animal models and asthma depends on interleukin-5 and a family of chemokines named eotaxins, comprising CCL11, CCL24 and CCL26. Up-regulation of CCL11 has been described in BP, but the expression of the other two members of the eotaxin-family, CCL24 and CCL26, has not been investigated. In addition to these chemokines, expression of adhesion molecules associated with eosinophil migration to the skin should be analysed. We demonstrate that similar to CCL11, the concentration of CCL26 was up-regulated in serum and blister fluid of BP patients. In contrast, the concentration of CCL24 was not elevated in sera and blister fluid of the same BP patients. In lesional skin, CCL11 and CCL26 were detected in epidermis and dermis by immunohistochemistry. In contrast to CCL11, CCL26 was expressed strongly by endothelial cells. In line with these findings, eosinophils represented the dominating cell population in BP lesional skin outnumbering other leucocytes. The percentage of eosinophils expressing very late antigen (VLA): VLA-4 (CD49d) and CD11c correlated with their quantity in tissue. Macrophage antigen (MAC)-1 (CD11b/CD18) was expressed constitutively by tissue eosinophils. In conclusion, these data link the up-regulation of the eosinophil chemotactic factor CCL26 in BP to the lesional accumulation of activated eosinophils in the skin. Thereby they broaden the understanding of BP pathogenesis and might indicate new options for therapeutic intervention.

Distinct CSF cytokine/chemokine profiles in atopic myelitis and other causes of myelitis

We reported the emergence of a distinct myelitis in patients with atopic diathesis (atopic myelitis [AM]) by a nationwide survey throughout Japan. Similar cases have recently been reported in Caucasians. Pathologic studies of biopsied spinal cord specimens revealed chronic active inflammation with eosinophilic infiltration. To clarify the cytokine/chemokine alterations in CSF from patients with AM in comparison to other causes of myelitis. We measured 27 cytokines, chemokines, and growth factors simultaneously in CSF from 22 patients with AM, 20 with opticospinal multiple sclerosis (OSMS), 11 with HTLV-1-associated myelopathy (HAM), 9 with Sjögren syndrome-related myelitis (SM), and 20 with other noninflammatory neurologic diseases (OND), using a fluorescent bead-based immunoassay. In patients with AM, CCL11 and interleukin (IL)-9 were significantly increased as compared with patients with OND and other myelitis while in patients with OSMS interferon-gamma and granulocyte-colony stimulating factor levels were significantly higher than in patients with OND and other causes of myelitis. Significant increase of IL-17 in comparison to patients with OND was found only in patients with OSMS, irrespective of presence or absence of anti-aquaporin-4 (AQP4) antibody. In patients with HAM, CXCL10 and CCL5 were higher than in patients with OND and other myelitis. In patients with SM, CCL3 and CCL4 were higher than in patients with OND. In patients with AM, CCL11, IL-9, and IL-1 receptor antagonist (IL-1ra) showed positive correlations with the final Kurtzke Expanded Disability Status Scale scores while IL-1ra and IL-12(p70) had positive correlations with disease duration. Intrathecal upregulation of CCL11 and Th2 cytokines is characteristic of atopic myelitis, which is distinct from interleukin-17/interferon-gamma-related autoimmune condition of opticospinal multiple sclerosis.

Rosmarinic acid as a downstream inhibitor of IKK-beta in TNF-alpha-induced upregulation of CCL11 and CCR3.

1. Tumor necrosis factor (TNF)-alpha is known to induce the expression of CCL11 and CCR3 via the activation of NF-kappaB. CCL11 (eotaxin), the C-C chemokine, is a potent chemoattractant for eosinophils and Th2 lymphocytes, and CCR3 is the receptor for CCL11. 2. In order to determine the effects of rosmarinic acid on the TNF-alpha-induced upregulation of CCL11 and CCR3 in human dermal fibroblasts, we performed an enzyme-linked immunosorbent assay for CCL11 and a Western blot assay for CCR3. The TNF-alpha-induced expression of CCL11 and CCR3 genes was attenuated by rosmarinic acid. 3. In our NF-kappaB luciferase reporter system, TNF-alpha-induced NF-kappaB activation was observed to be reduced by rosmarinic acid. In accordance with this result, rosmarinic acid also inhibited TNF-alpha-induced phosphorylation and degradation of IkappaB-alpha, as well as nuclear translocation of NF-kappaB heterodimer induced by TNF-alpha. This suggests that rosmarinic acid downregulates the expression of CCL11 and CCR3 via the inhibition of NF-kappaB activation signaling. 4. Using the NF-kappaB luciferase reporter system, Western blot analysis, and IKK-beta activity assay, we determined that rosmarinic acid inhibits IKK-beta activity in NF-kappaB signaling, which upregulates the expression of CCL11 and CCR3. Additionally, TNF-alpha-induced secretion of soluble intercellular adhesion molecule-1 and soluble vascular cell adhesion molecule-1 molecules was found to be attenuated by rosmarinic acid. 5. Our results show that rosmarinic acid inhibits the expression of CCL11 and CCR3 by suppressing the IKK-beta activity in NF-kappaB activation signaling. Further, these results suggest that rosmarinic acid might inhibit the expression of NF-kappaB promoter-related genes.