IgE-dependent activation of human mast cells and fMLP-mediated activation of human eosinophils is controlled by the circadian clock
Introduction
The circadian clock plays a key role in many physiological processes and behaviors such as in the maintenance and regulation of sleep–wake cycle, metabolism, or immunological processes (Reppert and Weaver, 2002). Interruption of circadian rhythms caused by sleep disturbances, jet lag or shiftwork resulted in biological and metabolic malfunction (De Bacquer et al., 2009), increased inflammation, emergence of malignant growth and cancer (Logan et al., 2012, Davis and Mirick, 2006, Filipski et al., 2003) as well as reduced life span.
The mammalian circadian clockwork system consists of a core oscillator located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus and peripheral tissues (Froy and Chapnik, 2007, Reppert and Weaver, 2002). At the molecular level, generation of circadian rhythms is maintained by the expression of specific clock genes, and thus, the functional interaction of transcriptional and translational feedback loops. Briefly, the transcription factor circadian locomotor output cycles Kaput (CLOCK) forms a heterodimer with brain and muscle ARNT-like protein 1 (BMAL1) to activate the transcription of several genes, including Periods 1–3 (Per1, Per2, Per3) and Cryptochromes 1–2 (Cry1, Cry2) as well as clock controlled genes, upon binding to E-box containing (5′-CACGTG-3′) sequences. PER and CRY proteins oligomerize and migrate to the nucleus to act as transcription repressors resulting in the inhibition of CLOCK:BMAL1-mediated transcription (Reppert and Weaver, 2001).
The prevalence of allergic diseases, such as atopic dermatitis, asthma or allergic rhinitis has rapidly increased in the past decades especially in industrialized countries. The severity of major symptoms of allergic diseases as well as pulmonary function are frequently exacerbated between midnight and morning and exhibit a prominent 24 h variation (Smolensky et al., 2007, Durrington et al., 2014). These findings assume a role for the biological clock in allergic reactions and a novel approach of new therapeutic strategies and appropriate treatment within chronopharmacology.
Mast cells (MC) and eosinophils are known to be involved as major effector cells in type I allergic reactions, and in many other acute and chronic diseases (Minai-Fleminger and Levi-Schaffer, 2009, Bischoff, 2007). Within the allergic response, MC carry out their inflammatory effects by producing and releasing a variety of pre-stored (histamine, β-hexosaminidase or proteases) as well as de novo synthesized mediators, such as lipid mediators, proinflammatory cytokines and chemokines in response to activation via the high-affinity FcɛRI (Bischoff, 2007). Eosinophils are capable of producing the granule-stored proteins major basic protein (MBP), eosinophil peroxidase (EPO), eosinophil cationic protein (ECP), and eosinophil-derived neurotoxin/eosinophil protein X (EDN/EPX) as well as lipid mediators, growth factors, proinflammatory chemokines and cytokines (Kariyawasam and Robinson, 2006, Hogan et al., 2008).
A circadian variation of serum mast cell tryptase (Dugas-Breit et al., 2005) and plasma histamine (Friedman et al., 1989) concentrations with lower levels in the afternoon and nocturnal peaks has been reported. Several studies suggested that some eosinophil-specific mediators, including ECP, and EPX/EDN displayed a diurnal variation in sputum, urine and serum in patients with allergic rhinitis (Wolthers and Heuck, 2003). Recently, we demonstrated a functional circadian clock in human MC and eosinophils. Clock genes as well as mast cell-specific molecules, such as tryptase, FcɛRI α-chain and cKit were expressed in a circadian manner (Baumann et al., 2013). Similarly, an oscillatory expression pattern of the eosinophil-specific molecules ECP and EPX/EDN was observed in human eosinophils.
The aim of this study was to analyze the role of the molecular clock in the functionality of MC and eosinophils in response to activation and consequently, their relevance in allergic reactions.
Section snippets
Isolation and culture of human intestinal mast cells
Human intestinal mast cells (hiMC) were isolated from intestinal mucosa of macroscopically normal surgery specimens of patients who underwent bowel resection because of cancer. Intestinal tissue is a good source to obtain primary human MC. The procedure of combined mechanic and enzymatic tissue digestion is described in detail elsewhere (Sellge and Bischoff, 2006). The study has been approved by the local ethics committee. The obtained cell suspension was cultured overnight in medium RPMI 1640 +
Clock genes oscillate in IgE-activated hiMC
We have recently demonstrated that MC isolated from intestinal tissue featured an intact molecular clock. All examined core clock genes, including hPer1, hPer2, hBmal1, hClock, and hCry1 were expressed and showed rhythmic oscillation in unstimulated hiMC (Baumann et al., 2013). Based on these findings, we set out to establish whether FcɛRI-mediated activation of hiMC influences the expression of clock genes. HiMC synchronized with dexamethasone were untreated or activated by FcɛRI crosslinking
Discussion
In this study, we observed that elementary components of the circadian clock reveal circadian expression in both unstimulated and activated human MC and eosinophils. Moreover, we could demonstrate that proinflammatory mediators such as the chemokines CXCL8 and CCL2 are expressed and secreted in a circadian fashion by hiMC and eosinophils in response to activation. These results emphasize an important role of the biological clock in allergic disorders. Indeed, allergic diseases such as allergic
Conflicts of interest
All authors declare that there are no conflicts of interest.
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (LO 581/7-1 to Axel Lorentz and Oren Froy). The authors thank Yvonne Soltow for excellent technical assistance.
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