CCL8
C-C motif chemokine 8 precursor (HC14) (Monocyte chemoattractant protein 2) (Monocyte chemotactic protein 2) (MCP-2) (Small-inducible cytokine A8) [Contains: MCP-2(6-76)] [MCP2] [SCYA10] [SCYA8]
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Age-related alterations in immunity have been linked to increased incidence of infections and decreased responses to vaccines in the aging population. Human peripheral blood monocytes are known to promote Ag presentation and antiviral activities; however, the impact of aging on monocyte functions remains an open question. We present an in-depth global analysis examining the impact of aging on classical (CD14 CD16 ), intermediate (CD14 CD16 ), and nonclassical (CD14 CD16 ) monocytes. Monocytes sorted from nonfrail healthy adults (21-40 y) and old (≥65 y) individuals were analyzed after stimulation with TLR4, TLR7/8, and retinoic acid-inducible gene I agonists. Our data showed that under nonstimulated conditions, monocyte subsets did not reveal significant age-related alternations; however, agonist stimulated-monocytes from adults and old subjects did show differences at the transcriptional and functional levels. These alternations in many immune-related transcripts and biological processes resulted in reduced production of IFN-α, IFN-γ, IL-1β, CCL20, and CCL8, and higher expression of CX3CR1 in monocytes from old subjects. Our findings represent a comprehensive analysis of the influence of human aging on pattern recognition receptors signaling and monocyte functions, and have implications for strategies to enhance the immune response in the context of infection and immunization.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Cytokines
- Female
- GPI-Linked Proteins
- Gene Expression Profiling
- Humans
- Immunity, Innate
- Interferons
- Lipopolysaccharide Receptors
- Male
- Middle Aged
- Monocytes
- Receptors, IgG
- Receptors, Pattern Recognition
- Toll-Like Receptor 4
- Toll-Like Receptor 7
- Toll-Like Receptor 8
- Transcription, Genetic
- Young Adult
Ionizing radiation has been demonstrated to result in degranulation of dermal mast cells. Chemokines are thought to play a crucial role in the early phase of the cutaneous radiation reaction. In human skin, mast cells are located in close proximity to dermal fibroblasts, which thus are a potential target for the action of mast cell mediators. In this study, we evaluated the effects of mast cell-derived histamine, serotonin, tumour necrosis factor (TNF)-α and tryptase on chemokine release from dermal fibroblasts. Human mast cells (HMC-1) were investigated for histamine release and cytokine production after ionizing radiation using enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Receptor expression on human fetal foreskin fibroblasts (HFFF2) and human adult skin fibroblasts (HDFa) was examined by flow cytometry. Chemokine mRNA and protein expression were analyzed by gene array and ELISA, respectively. Ionizing radiation significantly increased histamine release and cytokine expression by HMC-1 cells. Receptors for histamine, serotonin, TNF-α and tryptase were detected both in HFFF2 and in HDFa cells. Dermal fibroblasts constitutively expressed distinct sets of chemokine mRNA. Mast cell mediators differentially affected the release of chemokines CCL8, CCL13, CXCL4 and CXCL6 by fibroblasts. Our data suggest that radiation-induced mast cell mediators have a tremendous impact on inflammatory cell recruitment into irradiated skin. We postulate the activation of mast cells to be an initial key event in the cutaneous radiation reaction, which might offer promising targets for treatment of both normal tissue side effects in radiation therapy and radiation injuries.
MeSH Terms
- Aging
- Cell Communication
- Cell Line
- Cells, Cultured
- Chemokines
- Cytokines
- Dermis
- Fibroblasts
- Histamine
- Humans
- Mast Cells
- Serotonin
- Tryptases
- Tumor Necrosis Factor-alpha