Mechanisms of eosinophil cytokine release

Abstract

Human eosinophils have been demonstrated to contain a multitude of cytokines and chemokines that exist preformed within these cells. This content of pre-formed cytokines, with diverse potential biologic activities, provides eosinophils with capabilities distinct from most other leukocytes. The localization of pre-formed cytokines within eosinophils is both within specific granules and associated with substantial numbers of morphologically distinct cytoplasmic vesicles. Stimulation for release of specific cytokines, such as IL-4, leads to a regulated signal transduction cascade, which is dependent on the formation of leukotriene C 4 within eosinophils where it acts as an intracrine mediator. IL-4 release occurs selectively and is by means of vesicular transport. The capabilities of eosinophils not only to rapidly release pre-formed cytokines but also to differentially regulate which cytokines are released endow eosinophils with distinct abilities in innate and acquired immunity.Key words: eosinophils -cytokines -degranulation BackgroundEosinophil specific granules contain four distinct cationic proteins, named major basic protein (MBP), eosinophil peroxidase (EPO), eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN), whose extracellular release may cause dysfunction and destruction of surrounding cells (reviewed Gleich et al. 1992). In addition to these toxic proteins, eosinophil specific granules also store at least two-dozen of pre-formed cytokines and chemokines with pro-inflammatory or immunoregulatory properties. By a variety of techniques, such as subcellular fractionation, immunogold electron microscopy, and immunocytochemistry, a growing list of cytokines has been found within human eosinophil granules, including: (a) prototypical Th1 cytokines: IL-12 (Grewe et al. 1998) and IFN-γ (Lamkhioued et al. 1996); (b) prototypical Th2 cytokines: IL-4 (Moller et al. 1996b), IL-5 (Dubucquoi et al. 1994, Moller et al. 1996a, Desreumaux et al. 1998) and IL-13 (Woerly et al. 2002); (c) chemokines: RANTES , Ying et al. 1996, IL-8 (Braun et al. 1993), and eotaxin (Nakajima et al. 1998); (d) growth factors: granulocyte/macrophage colony-stimulatin factor (GM-CSF) (Levi-Schaffer et al. 1995, Desreumaux et al. 1998, IL-3 (Desreumaux et al. 1998), vascular endothelial growth factor (VEGF) (Horiuchi & Weller 1997), transforming growth factor (TGF)-α (Egesten et al. 1996) and stem cell factor (SCF) (Hartman et al. 2001); (e) pro-inflammatory cytokines: tumor necrosis factor (TNF)-α (Beil et al. 1993) and IL-6 (Lacy et al. 1998); and (f) immune-regulators: IL-16 (Lim et al. 1996), IL-2, and IL-10 (Woerly et al. 1999).In view of such diverse functional potentiality, eosinophil degranulation is a critical process by which eosinophils may damage, activate or down-regulate the neighboring cells. Hence, it was hypothesized that not all granule proteins are concomitantly released from eosinophils. Conversely, a regulated mechanism to specifically select and release proteins from eosinophil granules may exi...

The Regulatory Function of Eosinophils

“…Gene deletion studies in mice have also indicated that disruption of EPO or MBP results in significantly higher worm burdens compared to wildtype mice (40). The key activating signal for promoting these responses is not agreed upon yet, but multiple lines of evidence suggest that functional Fc receptors on eosinophils (allowing mediation of antibody-dependent cellular cytotoxicity), complement receptors and several receptors for pathogen/damage-associated molecular patterns (PAMP/DAMP) may contribute (41, 42). …”

Leukocyte lipid bodies — Biogenesis and functions in inflammation

“…Cytokines and chemokines are produced and secreted by a variety of activated leukocytes including macrophages, neutrophils, mast cells, basophils and eosinophils. In addition to their ability to synthesize new cytokine proteins, leukocytes also contain cytokines as stored, preformed pools that can be found within a variety of cellular compartments, including granules, vesicles and lipid bodies [138]. Tumor necrosis factor-alpha (TNF-α) was the first cytokine found within lipid bodies, detected throughout cytoplasmic lipid bodies cores by immune gold EM of different cell types present in colonic Crohn’s disease biopsies, including infiltrating neutrophils, macrophages and eosinophils [139].…”

Eosinophil granules function extracellularly as receptor-mediated secretory organelles

“…6) and not IL-8, IL-10, or IL-12 (p70) from isolated granules. Thus, agonistdependent processes mediating eosinophil cytokine secretion by cell-free granules can be selective, as demonstrated with intact eosinophils (4,20,21), providing novel insights into the potential regulated capabilities of eosinophil granules, when released extracellularly, to be variably responsive to cytokine, chemokine, and other agonists in differentially secreting their granule-stored proteins.…”