Catecholamines Inhibit IL-27 Production

First Evidence that Catecholamines Inhibit IL-27 Production by Antigen Presenting Cells

Catecholamines Inhibit IL-27 Production

A recent J. Immunology study provides perhaps the first evidence that catecholamines such as norepinephrine and epinephrine inhibit the production of interleukin-27 (IL-27) via the activation of β2-adrenoceptors, and by mechanisms involving IL-10 and the JNK signaling pathway.

Homeostasis within the immune system is largely dependent on cytokines, the ‘hormones’ of the immune system that control immune and inflammatory responses. Immunogenetic and neurohormonal mechanisms are known to influence cytokine profiles and production.

The neurohormonal control is exerted by the neuroendocrine humoral outflow via the pituitary and the autonomic nervous system (ANS) via direct neuronal influences. The sympathetic nervous system (SNS), a major part of the ANS, innervates all primary and secondary lymphoid organs. The catecholamines such as norepinephrine (noradrenaline), epinephrine (adrenaline) and dopamine, along with NPY and ATP represent the major SNS neuromediators and neurotransmitters.

IL-27, a cytokine identified in 2002, is a member of the IL-12 and IL-6 cytokine families, and the group of dimer cytokines that include IL-12, IL-23 and IL-35. It consists of the signature subunit p28 (IL-27p28), and a second subunit, the EBV-induced gene 3 (EBI3), which is shared with heterodimeric IL-35 (EBI3/p35).

IL-27 displays pleiotropic functions involving immune-enhancing, immune-regulatory and anti-inflammatory effects.

The immune-enhancing activities of IL-27 include the promotion of clonal expansion of naïve CD4+ T cells, and the IL-27 mediated Th1 polarization and IFN- production in naïve CD4+ T cells.

On the other hand, IL-27 has anti-inflammatory and immune-regulatory functions and inhibits Th2, innate lymphoid cell-2 (ILC2), and Th17 responses.

Importantly, IL-27 stimulates CD4+ T cells to express the immuneregulatory and anti-inflammatory cytokine IL-10. Thus, a major function of IL-27 following ligation to the IL-27RA/gp130 receptor complex on various T cell subsets include the activation of JAK1/2, asymmetric STAT1/STAT3, and Egr-2 signaling pathways culminating in the release of IL-10.

IL-27 also stimulates dendritic cells’ induction of the immunoregulatory molecule CD39. Thus, it looks like that IL-27 is as a major T cell–suppressive cytokine required for regaining immune homeostasis following clearance of infections and for preventing T cell–mediated lethal inflammation.

In general, IL-27 promotes the differentiation of Th1 and Tr1 cells, but inhibits the differentiation of Th2, Th17, and Treg cells.

In the J. Immunology study, Julian Roewe and colleagues from the University Medical Center, Johannes Gutenberg University Mainz in Germany demonstrate that the catecholamines norepinephrine (noradrenaline) and epinephrine (adrenaline) are able to inhibit the IL-27 release by LPS/TLR4-activated macrophages.

This is achieved by the stimulation of β2-adrenoceptors expressed on these cells. This effect appears to be dependent on an inhibitory feedback loop related to IL-10. Importantly, β2-adrenoceptors agonists in combination with IL-10 down-regulate the IL-27–stimulating intracellular JNK signaling pathway.

The authors discuss that the “fine-tuning of IL-27–dependent immune responses by catecholamines presumably relays multilayered context-dependent influences on the prevailing inflammatory states”.

Furthermore, as IL-27 has been suggested as a biomarker for the diagnosis of sepsis patients, according to the authors, the catecholamine therapy often used in this condition, may in fact represent a confounding factor and may distort IL-27 concentrations.

Thus, future studies related to the functional consequences and the implications of the above-described observations, are warranted.

Source: J Immunol, 2017, 199(7):2503-2514. doi: 10.4049/jimmunol.1700687. Epub 2017 Aug 23.
Read More: J. Immunology

Further Readings: The sympathetic nerve–an integrative interface between two supersystems: the brain and the immune system
Adrenergic modulation of dendritic cells function: relevance for the immune homeostasis
Sympathetic neural-immune interactions regulate hematopoiesis, thermoregulation and inflammation in mammals

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