Bone Marrow-Derived Dendritic Cells Primed – Epinephrine
A study published in the journal Brain, Behavior, and Immunity indicates that the stress hormone epinephrine (also known as adrenaline) is able to drive a Th2/Th17-shift in dendritic cells (DCs) in the presence of a pathogenic stimulus.
Mechanisms which drive imbalanced CD4+ T cellular responses play an important role in the initiation and progression of several chronic diseases. Thus, polarized Th2 cellular activation is known to exacerbate allergic asthma, but individuals who suffer from rheumatoid arthritis have documented elevations in Th1-mediated inflammatory responses. Recent evidence indicates a significant role of Th17 as well as T regulatory cell activation in chronic inflammatory conditions.
Dendritic cells cytokine and chemokine profiles are able to shape CD4+ T cell pathways and phenotypes and thus affect several T cell-related inflammatory conditions. DC-associated IL-12 and IL-23 cytokine production has a key role in dictating DC ability to instruct CD4+ T cell phenotypes.
IL-12 is a heterodimeric cytokine comprising of covalently linked p40 and p35 subunits and is widely known to promote the differentiation of Th1 effector cells.
More recently, a novel subunit p19 that associates with the IL-12p40 subunit was discovered. Similar to IL-12, IL-23 cytokine production requires both p19 and shared p40 subunit expression. Importantly, the production of IL-23 by DC is crucial for the regulation of IL-17 production by CD4+ T cells.
More recently, a novel subunit p19 that associates with the IL-12p40 subunit was discovered. Similar to IL-12, IL-23 cytokine production requires both p19 and shared p40 subunit expression. Importantly, the production of IL-23 by DC is crucial for the regulation of IL-17 production by CD4+ T cells.
Of note, IL-17 plays a pivotal role in the regulation of chemokines and adhesion molecules associated with the infiltration of neutrophils to inflammatory sites, through binding of its receptor on epithelial cells and endothelial cells.
In the Brain, Behavior, and Immunity study, Byung-Jin Kim and Harlan Jones address the effect of adrenal medullary stress hormone epinephrine on DCs behavior.
The authors demonstrate that epinephrine exposure contributes to LPS-induced increase in surface CD80, CD86 and MHCII expression. Such findings demonstrate the potential relevance of epinephrine’s influence during the initial stages of DC activation and maturation independent of antigen exposure. In that epinephrine exposure enhanced MHCII as well as CD80 and CD86 co-stimulatory molecule expression suggests that epinephrine supports an elevated DC activation status.
The investigators show that exposing murine bone marrow-derived dendritic cells (BMDC) to epinephrine then bacterial lipopolysaccharide (LPS) induces a preferential reduction in IL-12p40 mRNA transcripts, but an increase of IL-23p19 and IL-12p35 mRNA expression, associated with a decrease of IL-12p70 and a concomitant increase in IL-23 and IL-10 cytokine production.
IL-10, a key facilitator of Th2 and regulatory CD4+T cells responses is found prevalent in many chronic inflammatory disease states. These changes correspond with increased IL-4 and IL-17A, but not IFN-gamma cytokine production by CD4+ T cells.
The authors note that most striking was the ability of LPS-stimulated BMDC to facilitate de novo IL-17A by CD4+ T cells independent of CD3-stimulation at levels significantly higher than IFN-γ. Moreover, epinephrine was found to significantly increase this response that was reversed by butoxamine treatment. This study is perhaps the first to test IL-17A cytokine production by a mix resting population of CD4+ T cells in the absence of TCR-mediated activation in the context of LPS-associated TLR-4 DC activation. This suggests a potentially novel mechanism in which epinephrine action on DC in the presence of TLR activation constitutes a default toward IL-17A.
According to the authors, these results suggest that exposure to stress-derived epinephrine dictates dendritic cells to generate a dominant Th2/Th17 phenotype in the context of subsequent exposure to a pathogenic stimulus. Thus, the adrenergic stimulation can affect inflammatory conditions by favoring Th17 differentiation through augmentation of DC cytokine functioning.
In summary, DC function represented by the type of cytokines and chemokines they secrete is critical for programming the type and quality of CD4+ T cell responses. Importantly, because inflammatory conditions mediated by CD4+ T cells require DC regulation, understanding the mode of action will likely benefit the development of therapies which control chronic disease. In recent years, the IL-17 cytokine family has become the center of attention in regulation of inflammatory disease states including arthritis, colitis, asthma and cardiovascular disease
The results in this study suggest that adrenergic stimulation can affect inflammatory conditions by favoring Th17 differentiation through augmentation of DC cytokine functioning. The authors hypothesize that differential pathways can be driven by epinephrine through selectivity of β2-adrenergic responses that can result in CD4+ T cell cytokine production by non-classical DC-CD4+ T cell interaction.
Since the IL-17 cytokine family has been recently implicated in the pathogenesis of several chronic inflammatory diseases, these findings may provide further insights into the role of stress in the exacerbation of these inflammatory conditions.
Source: Brain Behav Immun 2010, 24: 1126
