Hypothalamo-pituitary and immune-dependent adrenal regulation during systemic inflammation

Waldemar Kanczkowski, Vasileia Ismini Alexaki, Nguyen Tran, Sylvia Großklaus, Kai Zacharowski, Antoine Martinez, Petra Popovics, Norman L. Block, Triantafyllos Chavakis, Andrew V. Schally, Stefan R. Bornstein

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45 Scopus citations

Abstract

Inflammation-related dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is central to the course of systemic inflammatory response syndrome or sepsis. The underlying mechanisms, however, are not well understood. Initial activation of adrenocortical hormone production during early sepsis depends on the stimulation of hypothalamus and pituitary mediated by cytokines; in late sepsis, there is a shift from neuroendocrine to local immune-adrenal regulation of glucocorticoid production. Therefore, the modulation of the local immune-adrenal cross talk, and not of the neuroendocrine circuits involved in adrenocorticotropic hormone production, may be more promising in the prevention of the adrenal insufficiency associated with prolonged sepsis. In the present work, we investigated the function of the crucial Toll-like receptor (TLR) adaptor protein myeloid differentiation factor 88 (MyD88) in systemic and local activation of adrenal gland inflammation and glucocorticoid production mediated by lipopolysachharides (LPSs). To this end, we used mice with a conditional MyD88 allele. These mice either were interbred with Mx1 Cre mice, resulting in systemic MyD88 deletion, predominantly in the liver and hematopoietic system, or were crossed with Akr1b7 Cre transgenic mice, resulting thereby in deletion of MyD88, which was adrenocortical-specific. Although reduced adrenal inflammation and HPA-axis activation mediated by LPS were found in Mx1(Cre+)-MyD88(fl/fl) mice, adrenocortical-specific MyD88 deletion did not alter the adrenal inflammation or HPA-axis activity under systemic inflammatory response syndrome conditions. Thus, our data suggest an important role of immune cell rather than adrenocortical MyD88 for adrenal inflammation and HPA-axis activation mediated by LPS.

Original languageEnglish (US)
Pages (from-to)14801-14806
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number36
DOIs
StatePublished - Sep 3 2013

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Keywords

  • adrenal gland insufficiency
  • the HPA axis
  • Toll-like receptors

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kanczkowski, W., Alexaki, V. I., Tran, N., Großklaus, S., Zacharowski, K., Martinez, A., Popovics, P., Block, N. L., Chavakis, T., Schally, A. V., & Bornstein, S. R. (2013). Hypothalamo-pituitary and immune-dependent adrenal regulation during systemic inflammation. Proceedings of the National Academy of Sciences of the United States of America, 110(36), 14801-14806. https://doi.org/10.1073/pnas.1313945110