Hormokines : a novel concept of plasticity in neuro-endo-immunology

Hormones are produced by endocrine and neuroendocrine cells and mediate mainly
systemic effects. Cytokines are produced by numerous cell types and mediate local
effects. The production of calcitonin (CT) peptides follows either the classical
hormonal expression which is believed important for calcium metabolism or cytokinelike
expression which is induced by inflammatory stimuli. To describe this plasticity,
the term “hormokine” was proposed.
The concept is based on the discovery of the ubiquitous expression of CT peptides
(i.e., ProCT, CT gene-related peptide (CGRP) and adrenomedullin (ADM)) during
sepsis. Using human mesenchymal stem cell (MSC) - and preadipocyte- derived
mature adipocytes it was shown in this thesis study that different CT peptides are
differentially regulated upon inflammatory stimuli and mediate distinct metabolic
effects. Especially ProCT appeared to be a pivotal mediator during sepsis. Based on
the findings, a trimodal expression pattern of the CALC I gene and a closely related
biphasic behavior of infection-related ProCT secretion was postulated. The exact
mode of actions of hormokines in the context of inflammation and infection remains
enigmatic. Based on the structural homologies, different CT peptides have
overlapping bioactivities, which they exert by binding to the same family of receptors.
For example CGRP and ADM contribute to vasoregulation in inflammatory conditions
and were found to modulate their own expression and bioactivities.
In a second phase of the thesis, the concept of hormokines was extended to the
hypothesis, that other hormones can also be regulated and act as hormokines. In this
context, an upregulation of somatostatin (SRIF) upon inflammatory stimulation was
observed in human adipose tissue.
Because of the hormokine like behavior of SRIF, also an islet hormone, the idea
arose that other islet hormones (e.g. insulin, glucagon) could be expressed
ectopically. In this context, the plasticity of the neuro-endocrine phenotype was
documented by experiments indicating that progenitor cells can adopt an islet-like
phenotype upon differentiation and stimulation. Bone marrow derived MSCs and
human adipose tissue derived preadipocytes were shown to be able to form islet-like
clusters within days and recapitulate the sequential expression of key genes
observed during endocrine pancreatic development.
To better investigate hormones and hormokines a procedure to transduce mature
human adipocytes was established using lentiviral vectors.