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.
authors: Department of Medicine III, Technical University Dresden, 01307 Dresden, Germany.
authors: Waldemar
authors: W
authors: Kanczkowski
authors: Vasileia-Ismini
authors: VI
authors: Alexaki
authors: Nguyen
authors: N
authors: Tran
authors: Sylvia
authors: S
authors: Großklaus
authors: Kai
authors: K
authors: Zacharowski
authors: Antoine
authors: A
authors: Martinez
authors: Petra
authors: P
authors: Popovics
authors: Norman L
authors: NL
authors: Block
authors: Triantafyllos
authors: T
authors: Chavakis
authors: Andrew V
authors: AV
authors: Schally
authors: Stefan R
authors: SR
authors: Bornstein
mesh_terms: D000302:Adrenal Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000449:Aldehyde Reductase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005938:Glucocorticoids / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000502:physiology*; D064547:Myxovirus Resistance Proteins / Q000235:genetics / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D054426:Chemokine CXCL2; D005938:Glucocorticoids; D008070:Lipopolysaccharides; C579070:Mx1 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D064547:Myxovirus Resistance Proteins; D051193:Toll-Like Receptors; C118897:peptidoglycan recognition protein; C066498:Akr1b7 protein, mouse; D000449:Aldehyde Reductase
keywords: Toll-like receptors; adrenal gland insufficiency; the HPA axis
references: N Engl J Med. 2009 May 28;360(22):2328-39
references: 19474430
references: J Endocrinol. 2004 May;181(2):207-21
references: 15128270
references: Endocrinology. 2013 Mar;154(3):1181-9
references: 23364949
references: Mol Cell Endocrinol. 2009 Mar 5;300(1-2):197-204
references: 19041690
references: Horm Metab Res. 1998 Jun-Jul;30(6-7):416-20
references: 9694572
references: Int Immunol. 2000 Jan;12(1):113-7
references: 10607756
references: Mol Psychiatry. 2008 May;13(5):480-97
references: 18180766
references: Endocrinology. 1991 Jul;129(1):330-8
references: 1647300
references: Am J Respir Crit Care Med. 2006 Dec 15;174(12):1319-26
references: 16973979
references: Mol Cell Endocrinol. 2013 May 22;371(1-2):228-35
references: 23295830
references: Crit Care Med. 2001 Jul;29(7 Suppl):S109-16
references: 11445744
references: Life Sci. 1998;62(19):1783-7
references: 9585109
references: Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6392-7
references: 16606831
references: J Immunol. 1996 Jul 1;157(1):291-6
references: 8683129
references: Ann N Y Acad Sci. 2006 Nov;1088:307-18
references: 17192576
references: Mol Cell Endocrinol. 2009 Mar 5;300(1-2):57-65
references: 19022344
references: Nat Cell Biol. 2007 Sep;9(9):1081-8
references: 17704767
references: Ann N Y Acad Sci. 2000;917:628-37
references: 11268391
references: Endocrinology. 2008 Apr;149(4):1436-50
references: 18174279
references: Science. 1995 Sep 8;269(5229):1427-9
references: 7660125
references: J Neuroendocrinol. 2005 Mar;17(3):152-60
references: 15796767
references: EMBO J. 2002 Apr 2;21(7):1782-90
references: 11927562
references: Am J Physiol. 1997 Dec;273(6):R1870-7
references: 9435639
references: J Neurosci. 2005 Feb 16;25(7):1788-96
references: 15716415
references: Endocrinology. 2005 Mar;146(3):1398-402
references: 15564329
references: J Endotoxin Res. 2003;9(1):3-24
references: 12691614
references: Endocr Rev. 1998 Apr;19(2):101-43
references: 9570034
references: Proc Natl Acad Sci U S A. 2004 Nov 23;101(47):16695-700
references: 15546996
references: Endocrinology. 2006 Sep;147(9):4445-53
references: 16777969
references: Methods. 2001 Dec;25(4):402-8
references: 11846609