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, 9 (4), e92325
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Human Astrocytes: Secretome Profiles of Cytokines and Chemokines

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Human Astrocytes: Secretome Profiles of Cytokines and Chemokines

Sung S Choi et al. PLoS One.

Abstract

Astrocytes play a key role in maintenance of neuronal functions in the central nervous system by producing various cytokines, chemokines, and growth factors, which act as a molecular coordinator of neuron-glia communication. At the site of neuroinflammation, astrocyte-derived cytokines and chemokines play both neuroprotective and neurotoxic roles in brain lesions of human neurological diseases. At present, the comprehensive profile of human astrocyte-derived cytokines and chemokines during inflammation remains to be fully characterized. We investigated the cytokine secretome profile of highly purified human astrocytes by using a protein microarray. Non-stimulated human astrocytes in culture expressed eight cytokines, including G-CSF, GM-CSF, GROα (CXCL1), IL-6, IL-8 (CXCL8), MCP-1 (CCL2), MIF and Serpin E1. Following stimulation with IL-1β and TNF-α, activated astrocytes newly produced IL-1β, IL-1ra, TNF-α, IP-10 (CXCL10), MIP-1α (CCL3) and RANTES (CCL5), in addition to the induction of sICAM-1 and complement component 5. Database search indicated that most of cytokines and chemokines produced by non-stimulated and activated astrocytes are direct targets of the transcription factor NF-kB. These results indicated that cultured human astrocytes express a distinct set of NF-kB-target cytokines and chemokines in resting and activated conditions, suggesting that the NF-kB signaling pathway differentially regulates gene expression of cytokines and chemokines in human astrocytes under physiological and inflammatory conditions.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. The purity of human astrocytes in culture exceeded 99% glial fibrillary acidic protein (GFAP) immunoreactivity-positive.
Astocytes shown are at the normal non-stimulated resting state. A: Phase contrast microscopy. B: Immunostaning with anti-GFAP antibody.
Figure 2
Figure 2. Proteome profiler array of human cytokines/chmokines.
The array is capable of detecting a panel of 36 cytokines, chemokines, and soluble mediators. Top panel shows expression of cytokines/chemokines in resting unstimulated human astrocyrtes, and middle panel shows expression of cytkines/chemokines in human astrocytes stimulated with IL-1β and TNF-α. Items circled in red are newly expressed cytokines in activated astrocytes and ones circled in blue are cytokines changed expression in activated aqstrocytes. In bottom panel, newly expressed cytokines and cytokines changed expression are listed separately.
Figure 3
Figure 3. Cytokines/chemokines changed their secretion levels in human astrocytes stimulated with IL-1β and TNF-α.
A: Forty five-fold increase in secertion of GM-CSF and twenty-fold increase in secretion of G-CSF are shown here. A minor reduction in expression of MCP-1 and MIF is also shown. B. Among the elevated levels of cytokines/chemokines in human astrocytes stimulated with IL-1β and TNF-α, upregulated expression of RANTES was the most prominent with more than 150-fold increase.
Figure 4
Figure 4. Molecular network showing cytokine and chemokine secretomes of human astrocytes.
Entrez Gene IDs corresponding to 14 upregulated and 2 downregulated cytokines in IL-1β/TNF-α-activated human astrocytes were imported into the Ingenuity Pathways Analysis (IPA). The most significant molecular network relevant to the imported genes (red arrows) is shown. NF-kB is highlighted by blue circle. CCL5 (RANTES), CCL3 (MIP-1α), CXCL1 (GROα), CSF2 (GM-CSF), CSF3 (G-CSF), IL1R and IL1RAP are indicated by red.

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Grant support

The present study was supported by the Korea Healthcare Technology R&D Project HI12C0167 (A120214) and Canadian Myelin Research Initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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