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

Research output: Contribution to journalArticle

40 Citations (Scopus)

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
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

Fingerprint

Myeloid Differentiation Factor 88
Inflammation
Sepsis
Systemic Inflammatory Response Syndrome
Glucocorticoids
Hematopoietic System
Adrenal Insufficiency
Toll-Like Receptors
Adrenal Glands
Adrenocorticotropic Hormone
Transgenic Mice
Hypothalamus
Alleles
Hormones
Cytokines
Liver

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., ... 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

Hypothalamo-pituitary and immune-dependent adrenal regulation during systemic inflammation. / Kanczkowski, Waldemar; Alexaki, Vasileia Ismini; Tran, Nguyen; Großklaus, Sylvia; Zacharowski, Kai; Martinez, Antoine; Popovics, Petra; Block, Norman L; Chavakis, Triantafyllos; Schally, Andrew V; Bornstein, Stefan R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 36, 03.09.2013, p. 14801-14806.

Research output: Contribution to journalArticle

Kanczkowski, W, Alexaki, VI, Tran, N, Großklaus, S, Zacharowski, K, Martinez, A, Popovics, P, Block, NL, Chavakis, T, Schally, AV & Bornstein, SR 2013, 'Hypothalamo-pituitary and immune-dependent adrenal regulation during systemic inflammation', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 36, pp. 14801-14806. https://doi.org/10.1073/pnas.1313945110
Kanczkowski, Waldemar ; Alexaki, Vasileia Ismini ; Tran, Nguyen ; Großklaus, Sylvia ; Zacharowski, Kai ; Martinez, Antoine ; Popovics, Petra ; Block, Norman L ; Chavakis, Triantafyllos ; Schally, Andrew V ; Bornstein, Stefan R. / Hypothalamo-pituitary and immune-dependent adrenal regulation during systemic inflammation. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 36. pp. 14801-14806.
@article{8a56c250fd3e4e118e3687ff909866bb,
title = "Hypothalamo-pituitary and immune-dependent adrenal regulation during systemic inflammation",
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.",
keywords = "adrenal gland insufficiency, the HPA axis, Toll-like receptors",
author = "Waldemar Kanczkowski and Alexaki, {Vasileia Ismini} and Nguyen Tran and Sylvia Gro{\ss}klaus and Kai Zacharowski and Antoine Martinez and Petra Popovics and Block, {Norman L} and Triantafyllos Chavakis and Schally, {Andrew V} and Bornstein, {Stefan R.}",
year = "2013",
month = "9",
day = "3",
doi = "10.1073/pnas.1313945110",
language = "English",
volume = "110",
pages = "14801--14806",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "36",

}

TY - JOUR

T1 - Hypothalamo-pituitary and immune-dependent adrenal regulation during systemic inflammation

AU - Kanczkowski, Waldemar

AU - Alexaki, Vasileia Ismini

AU - Tran, Nguyen

AU - Großklaus, Sylvia

AU - Zacharowski, Kai

AU - Martinez, Antoine

AU - Popovics, Petra

AU - Block, Norman L

AU - Chavakis, Triantafyllos

AU - Schally, Andrew V

AU - Bornstein, Stefan R.

PY - 2013/9/3

Y1 - 2013/9/3

N2 - 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.

AB - 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.

KW - adrenal gland insufficiency

KW - the HPA axis

KW - Toll-like receptors

UR - http://www.scopus.com/inward/record.url?scp=84897497194&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84897497194&partnerID=8YFLogxK

U2 - 10.1073/pnas.1313945110

DO - 10.1073/pnas.1313945110

M3 - Article

VL - 110

SP - 14801

EP - 14806

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 36

ER -