Human eosinophils constitutively express multiple Th1, Th2, and immunoregulatory cytokines that are secreted rapidly and differentially

Abstract

Eosinophils are innate immune leukocytes implicated in the initiation and maintenance of type 2 immune responses, including asthma and allergy. The ability to store and rapidly secrete preformed cytokines distinguishes eosinophils from most lymphocytes, which must synthesize cytokine proteins prior to secretion and may be a factor in the apparent Th2 bias of eosinophils. Multiple studies confirm that human eosinophils from atopic or hypereosinophilic donors can secrete over 30 cytokines with a varying and often opposing immune-polarizing potential. However, it remains unclear whether all of these cytokines are constitutively preformed and available for rapid secretion from eosinophils in the circulation of healthy individuals or are restricted to eosinophils from atopic donors. Likewise, the relative concentrations of cytokines stored within eosinophils have not been studied. Here, we demonstrate that human blood eosinophils are not singularly outfitted with Th2-associated cytokines but rather, constitutively store a cache of cytokines with nominal Th1, Th2, and regulatory capacities, including IL-4, IL-13, IL-6, IL-10, IL-12, IFN-gamma, and TNF-alpha. We demonstrate further rapid and differential release of each cytokine in response to specific stimuli. As agonists, strong Th1 and inflammatory cytokines elicited release of Th2-promoting IL-4 but not Th1-inducing IL-12. Moreover, a large quantity of IFN-gamma was secreted in response to Th1, Th2, and inflammatory stimuli. Delineations of the multifarious nature of preformed eosinophil cytokines and the varied stimulus-dependent profiles of rapid cytokine secretion provide insights into the functions of human eosinophils in mediating inflammation and initiation of specific immunity.

Human Eosinophils Exert TNF-α and Granzyme A-Mediated Tumoricidal Activity toward Colon Carcinoma Cells

“…Besides cationic proteins, other cytotoxic mediators potentially released by eosinophils are cytokines such as TNF (16,29). We could indeed detect TNF release after overnight culture of eosinophils with Colo-205 (Fig.…”

“…These cationic proteins have been described to exert cytotoxic properties for tumor cell lines with variable efficiency (15). Beside cytotoxic mediators, eosinophil granules contain multiple Th1, Th2, and immunoregulatory cytokines that are rapidly and selectively secreted (16). Among them, IFN, IFN-g, and TNF, which are known to play a major role during antitumor responses, are released by eosinophils (17,18).…”

Episodic angioedema with eosinophilia (Gleich syndrome) is a multilineage cell cycling disorder

“…Serum levels of type II cytokines, including the primary eosinophilopoietic cytokine, IL-5, were consistently elevated prior to the eosinophilia in all subjects and intracellular staining of mitogen-stimulated lymphocytes at the peak and nadir of the cycle demonstrated an increased capacity for producGleich syndrome is a multilineage cell cycling disorder haematologica | 2015; 100 (3) 305 + lymphocytes prior to the development of eosinophilia in two subjects, consistent with a primary role for lymphocytes in driving the eosinophilia in EAE. Since activated eosinophils are known to secrete a wide variety of mediators and cytokines, 22 including the neutrophil chemoattractant IL-8, 23 cyclic changes in eosinophil activation could, in turn, explain the variation in neutrophil counts. Although a primary stem cell disorder could also explain multilineage involvement in EAE, the bone marrow did not show changes in CD34 + cell numbers.…”

Anti-CD69 monoclonal antibody treatment inhibits airway inflammation in a mouse model of asthma

“…IL-5 is thought to be a crucial regulator of eosinophil proliferation in asthma and other allergic disease (Shen et al, 2003). IL-5 has been shown to activate eosinophils to produce more IL-5 (Spencer et al, 2009), thus forming a positive feedback loop to expand the eosinophil reservoir in peripheral blood and bone marrow reacting to the allergen challenge. IL-5 also regulates the expression of genes involved in growth, survival, and effector function of eosinophils (Takatsu and Nakajima, 2008;Han and Mosher, 2014).…”