Human cord blood-derived mast cells synthesize and release I-309 in response to IgE
Introduction
Mast cells are the central mediating cells of allergic reactions. Binding of allergen specific IgE to high affinity IgE receptor (FcεRI) and subsequent binding of allergen by the IgE causes receptor cross-linking and activation (Yong, 1997). This activation leads to the release of preformed mediators stored in secretory granules. Among these mediators are histamine and mast cell proteases such as tryptase and chymase (Yong, 1997). In addition, activation leads to the de-novo synthesis of other mediators such as leukotrienes and prostaglandins and the production and release of various cytokines and chemokines including tumor necrosis factor-α (TNF-α), granulocyte/macrophage colony-stimulating factor (GM-CSF), monocyte chemotractant protein-1 (MCP-1), interleukin-8 (IL-8) and interleukin-10 (IL-10) (Yong, 1997). The profile of mediators released from activated mast cells in vivo influences the responses of local structural cells but also profoundly contributes to the nature of inflammatory cell infiltrates (Yong, 1997).
Allergic diseases are generally characterized by two phases (Umetsu and DeKruyff, 1997). The early phase allergic response, such as the anaphylactic response, is likely directly manifested through release of preformed mediators from mast cells (Bingham and Austen, 2000). The second, or late phase, response is characterized by inflammatory cell infiltrate and the development of hyperreactivity of various tissues. The cellular influx promoted during the late phase includes eosinophils, T and B lymphocytes, mast cells, basophils and monocytes (Umetsu and DeKruyff, 1997). A prominent modulator of this overall inflammatory response is the CD4+ T-cell (Umetsu and DeKruyff, 1997). In particular, the T-cell component of allergic diseases, such as asthma and allergic rhinitis, is predominantly T-helper type 2 (TH2) cells Kaplan, 2001, Umetsu and DeKruyff, 1997. These TH2 cells elaborate a spectrum of cytokines and chemokines (namely IL-4, IL-13, IL-5 and eotaxin) that promote the infiltration of other cell types Kaplan, 2001, Umetsu and DeKruyff, 1997.
I-309 is a C-C chemokine that is the ligand for the chemokine receptor CCR8. I-309 is chemotactic for T-cells, particularly TH2 cells through restricted expression of the CCR8 receptor (Kaplan, 2001). It is postulated that I-309 plays a key role in the progression of various diseases such as asthma, which have a TH2 component. Indeed, a subpopulation of the T-cells infiltrating lung mucosa in allergen-challenged asthmatics express CCR8 (Panina-Bordignon et al., 2001).
In this report we describe the observation that human umbilical cord blood-derived mast cells (CBMCs) produce the T-cell chemotactic chemokine I-309 in response to FcεRI cross-linking. In addition we explore the observation that IgE can induce significant production of I-309, and other cytokines, in the absence of mast cell degranulation.
Section snippets
Reagents
All chemicals were purchased from Sigma (St. Louis, MO) unless otherwise noted. Tissue culture medium and fetal bovine serum (FBS) were purchased from Invitrogen/Life-Technologies (Carlsbad, CA). Stem cell factor (SCF), interleukin-6 (IL-6) and interleukin-4 (IL-4) were purchased from R&D Systems (Minneapolis, MN). Human IgE and sheep anti-human IgE (α-IgE) were purchased from Biodesign (Saco, MA).
Cord blood derived mast cells (CBMCs)
Human umbilical cord blood mononuclear progenitors (Poeitic Technologies, Gaithersburg, MD) were
I-309 gene expression in cord blood-derived mast cells
Microarray analysis revealed that I-309 RNA expression was increased approximately 9-fold in cord blood-derived mast cells (CBMCs) cultured with IL-4 and activated with IgE/α-IgE compared to resting cells (data not shown). Further characterization of I-309 gene expression was carried out in both primed (IgE alone) and activated (IgE followed by α-IgE) CBMCs.
CBMCs grown in the presence or absence of IL-4 were primed with IgE (1 μg/ml, 24 hr) and activated with α-IgE (10 μg/ml). Total RNA was
Discussion
This report demonstrates that human umbilical cord blood-derived mast cells are capable of secreting the T-cell chemotactic chemokine I-309. Not only did CBMCs secrete I-309 in response to activation of FcεRI by IgE/α-IgE but also by priming with IgE alone. The response to IgE was both dose and time dependent and was not accompanied by release of histamine from these cells. The upregulation of I-309 occurred at the level of transcript accumulation (as indicated by real-time PCR analysis) and
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2005, Advances in ImmunologyCitation Excerpt :The complete biological activities of the 2‐acetylated phospholipid analogs of PAF remain to be determined. Immunologic stimulation of human mast cells activates a specific program of gene expression leading to de novo synthesis of a wide spectrum of cytokines (IL‐3, IL‐5, IL‐6, IL‐13, IL‐16, IL‐18, IL‐25, TGF‐β, SCF, GM‐CSF, TNF‐α) (Bressler et al., 1997; Burd et al., 1995; Gauchat et al., 1993; Ohkawara et al., 1992; Okayama et al., 1998; Patella et al., 1998b; Pawankar et al., 1997; Rumsaeng et al., 1997) and chemokines (IL‐8/CXCL8, MIP‐1αCCL3, MCP‐1/CCL2, I‐309/CCL1) (Baghestanian et al., 1997; Gilchrest et al., 2003; Möller et al., 1993; Yano et al., 1997). Interestingly, SCF, the principal growth, differentiating, and chemotactic factor for mast cells (de Paulis et al., 1999; Tsai et al., 1991), is synthesized (Zhang et al., 1998) and released by lung mast cells (Patella et al., 1998b).