Cortisol Exerts Bi-Phasic Regulationof Inflammation in Humans
Mark P. Yeager, MDPatricia A. Pioli, PhDPaul M. Guyre, PhD
Dose-Response 2010
Glucocorticoid History and Physiology
Thomas Addison On the Constitutional
and Local Effects of Disease of the Suprarenal Capsules1855 monograph No extra-adrenal organ
morbidity/pathology “melasma suprerenale” Progressive languor
Addison died of ‘melancholia’ in 1860
Dose-Response 2010
Hans Selye, MD1907-1982
Austrian-born, 3rd generation physician
Early interest in the ‘shock response’ as reproducible
Leading researcher in ‘shock’ 1930’s-1940’s
Systematically investigated the the role of adrenal cortical hormones on shock response in vivo.
Dose-Response 2010
Injury (Shock) ResponseStress, 1950
Shock phase (General Alarm Reaction) Initial loss of adrenal cortical lipids
Countershock phase (General Adaptation Syndrome) Subsequent hypertrophy of adrenal cortex Without adrenal cortex, countershock phase does not
develop and animal dies General Adaptation Syndrome (GAS):
Any systemic stress elicits a similar syndrome The syndrome helps adaptation (survival) Adaptation causes disease
Dose-Response 2010
‘Relative Adrenocortical Insufficiency’
“Our work…is definitely indicative of the existence of a relativeadrenal cortical insufficiency in cases of shock…and clinical administration of cortin would seem promising in wound shock.”
“These experiments confirmed our belief that it is primarily an increased adrenal cortical secretion which is responsible for the development of resistance in the countershock phase.”
Selye H. Can Med Assoc J, July 1940Dose-Response 2010
Selye-Legacy
Coined the term ‘stress’ as it is used in contemporary, non-engineering settings
Identified the ‘stress response’ as a common response to any systemic stimulus
Determined that the ‘stress response’ of an organism can, and does, lead to disease
Profoundly wrong
Dose-Response 2010
“The Effect of a Hormone of the Adrenal Cortex and of (ACTH) on Rheumatoid Arthritis”
Hench et al, Proc Mayo Clinic, 1949Dose-Response 2010
Philip Hench, MD1950 (1 Year Later)
Stockholm, 1950: “Dr Hench. The Caroline Institute has decided to award this year’s Nobel Prize in Medicine to you…for your discoveries regarding the hormones of the adrenal cortex...and their biologic effects.”
Hans Selye was nominated for a Nobel Prize 3 times but never won the award.
Dose-Response 2010
Glucocorticoid Research 1950-2000
Virtually ALL of the clinical GC research has focused on anti-inflammatory or suppressive properties of GCs
Very little research has been done on supportive or stimulatory properties of GCs-Selye’s ‘resistance’
Dose-Response 2010
Glucocorticoid Physiologistsat Dartmouth
Alan U. Munck, PhD Third Century
Professor, DMS
Paul M. Guyre, PhD Professor of
Physiology, DMS
Dose-Response 2010
Unifying Hypothesis of GC Actions
“Activity of Defense Mechanism”: Permissive (anti-
Addisonian) Suppressive Stimulatory
Preparative (time)
Dose-Response 2010
In Vivo Exposure to High or Low Cortisol Has Bi-Phasic Effects on Inflammatory Response Pathways of Human Monocytes
Anesth Analg, 2008
What would happen if we depleted GC effects in vivo?
Would we uncover evidence of suppressive or stimulatory effects of diurnal cortisol?
Mechanism: block both cortisol receptor & synthesis
0.1 1 10 100
Free cortisol concentrations (nM)
SUPPRESSIVE ACTIONS
Activity of defense mechanism
Diurnal Variation Stress
PERMISSIVE/STIMULATORY ACTIONS
Dose-Response 2010
In Vivo Exposure to High or Low Cortisol Has Bi-Phasic Effects on Inflammatory Response Pathways of Human Monocytes
Anesth Analg, 2008
Day 1 Day 2 Day 3 Day 4 Tim e-- > 7AM 4AM 7AM Noon 4PM 7PM 7AM 7AM Bloo d
sampling X X X X X
TREATM ENT S T reatme nt A - Co nt ro l
Placebo Placebo Placebo
Saline Saline i nfusion
T reatme nt B-Hi corti sol
Placebo Placebo Placebo
Hydro cor tisone 8 ug/kg / min iv HC p.o.
T reatme nt C-Lo Corti sol
RU486 RU486 RU486
Et omidat e 0.15 ug/kg/ hr
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In Vivo Exposure to High or Low Cortisol Has Bi-Phasic Effects on Inflammatory Response Pathways of Human Monocytes
Anesth Analg, 2008
Plasma Cortisol
1
10
100
1000
1 2 3 4 5
Sample Times
Control
Lo Cort
Hi Cort
1a
*** ***
***
+++
+++
++
Salivary Free Cortisol (Mean +/- S.E.)
1
10
100
1000
1 2 3 4 5
Sample Times
Control
Lo Cort
Hi Cort
1b
+++
+++
*** ***
***
ACTH(Mean +/- S.E.)
0
20
40
60
80
100
120
140
160
180
Control Lo Cort Hi Cort
pg
/m
l
Sample 1Sample 4Sample 5
+++
1c
Dose-Response 2010
In Vivo Exposure to High or Low Cortisol Has Bi-Phasic Effects on Inflammatory Response Pathways of Human Monocytes
Anesth Analg, 2008
LPS Stimulated White Blood Cell (MO) Response (TNF-a Release) (Mean +/- S.E.)
0
200
400
600
800
1000
1200
1400
0.0 ng/ml 0.01 ng/ml 0.1 ng/ml 1.0 ng/ml
LPS Concentration
Before Depletion
After Depletion
4a
Dose-Response 2010
In Vivo Exposure to High or Low Cortisol Has Bi-Phasic Effects on Inflammatory Response Pathways of Human Monocytes
Anesth Analg, 2008
Glucocorticoid Receptor mRNA (Mean +/- S.E.)
0
1
2
3
4
5
6
7
8
9
10
Media LPS
Rela
tive G
R m
RN
A L
evels
Control
Low Cortisol
High Cortisol
3a
***
***
***
***
IL-10 mRNA (Mean +/- S.E.)
0
5
10
15
20
25
30
35
40
45
50
Media LPS
Rela
tive I
L-1
0 m
RN
A L
evels
Control
Low Cortisol
High Cortisol
3c
***
***
Suppressor of Cytokine Synthesis (SOCS) 3 mRNA (Mean +/- S.E.)
0
50
100
150
200
250
Media LPS
Rela
tive S
OC
S3
mR
NA
Levels
Control
Low Cortisol
High Cortisol
3d
***
***
Dose-Response 2010
Unifying Hypothesis of GC Actions
“Activity of Defense Mechanism”: Permissive (anti-
Addisonian) Suppressive Stimulatory
Dose-Response 2010
Cortisol Anti-inflammatory Effects are Maximal at Postoperative Plasma Concentrations
Yeager MP et al. Crit Care Med 2005.
1st Case CABG, Valve Etomidate to limit endogenous
synthesis Added back varying doses of cortisol
(SoluCortef) Cytokine response (IL-6, IL-10) Looking for evidence of GC-mediated
stimulation of inflammatory response
Dose-Response 2010
Cortisol Anti-inflammatory Effects are Maximal at Postoperative Plasma Concentrations.
Yeager MP et al. Crit Care Med 2005.
0
10
20
30
40
50
60
70
80
Base 45' Inc. 15' XC 1hCPB 2.5hCPB 4hCPB POD1 POD2
Cor
tisol
ug/
dl
Avg. Grp 1
Avg. Grp 2
Avg. Grp 3
Avg. Grp 4
Avg. Grp 5
Avg. Grp 6
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Cortisol Anti-inflammatory Effects are Maximal at Postoperative Plasma Concentrations
Yeager MP et al. Crit Care Med 2005.
Where is the Bell? GCs, when present
or administered coincident with an inflammatory stimulus, are anti-inflammatory in a dose-dependent manner.
ACUTE EFFECTS OF CORTISOL
on IL-6
R2 =
0
200
400
600
800
1000
1200
1400
0 10 20 30 40 50 60
Incresing Plasma Cortisol
ACUTE EFFECTS OF CORTISOL
on IL-10
R2 = 0.9779
0
100
200
300
400
500
600
700
800
900
0 10 20 30 40 50 60
Increasing Plasma Cortisol
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Unifying Hypothesis of GC Actions
“Activity of Defense Mechanism”: Permissive (anti-
Addisonian) Suppressive Stimulatory
Preparative (time)
Dose-Response 2010
Experimental Stress in HumansExperimental Endotoxemia
Bacterial endotoxin as a model of systemic inflammation in human volunteers: E.Coli (Lot EC-6; O:113) ‘US Standard Reference
Grade Endotoxin’ Pharmacy Development Service, Clinical Center,
NIH--arrives as lyophilized powder 2 ng/kg I/V--what happens?
Nothing for ~ 1 hour Headache, chills, myalgia, tachycardia, fever, lethargy Resolution in 4-6 hours
Dose-Response 2010
Pre-treatment With Stress Cortisol Enhances the Human Systemic Inflammatory Response to Bacterial Endotoxin
Yeager et al, Crit Care Med, In Press
MONDAY TUES WED FRI
n= 12/grp
8-9AM 9AM-----------
3PM
7-8AM 8AM
9AM 11AM Noon 2PM
6-7PM
GROUP 1
Pregnancy testa, I/V placement
Saline I/V
Vascular catheter placementb
LPS 2ng/kg I/V
Dischargec
GROUP 2
Pregnancy testa, I/V placement
Hydrocortisone 1.5 ug/kg/min I/V
Vascular catheter placementb
LPS 2ng/kg I/V
Dischargec
GROUP 3
Pregnancy testa, I/V placement
Hydrocortisone 3 ug/kg/min I/V
Vascular catheter placementb
LPS 2ng/kg I/V
Dischargec
Blood sampled
X
X X X X
I/V = intravenous LPS = lipopolysaccharide (E.Coli endotoxin)
Dose-Response 2010
Pre-treatment With Stress Cortisol Enhances the Human Systemic Inflammatory Response to Bacterial Endotoxin
Crit Care Med, 2009
Plasma IL-6 response to LPS P=0.004 Stress vs. Control
Dose-Response 2010
Pre-treatment With Stress Cortisol Enhances the Human Systemic Inflammatory Response to Bacterial Endotoxin
Crit Care Med, In Press
Plasma IL-10 response to LPS P=0.03 Stress vs. Control
Dose-Response 2010
The Bell CurveWhat would be the relationship between the free cortisol
concentration achieved on Day 1 to IL-6 Response on Day 2
Abscissa: Free cortisol at end of Day 1 infusion Ordinate: Total IL-6 release (AUC) on Day 2
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SUMMARY
Cortisol regulation of human inflammation: Is not fully represented by a linear anti-
inflammatory dose-response Is both dose (concentration) and time-
dependent Exhibits delayed (preparative) effects that
are bi-phasic: either suppressive or stimulatory depending on cortisol concentration
Dose-Response 2010
Clinical Remnants of Selye’s Work:Acute Addisonian Crisis
• 34 y.o. male with rheumatoid arthritis• Oral cortisone for 8 months• Hip surgery• Hypotensive immediately after surgery
and died• Autopsy: adrenal cortical atrophy
Fraser et al. JAMA, 1952
Dose-Response 2010
What is a ‘Physiologic’ Cortisol Response to Acute Systemic Stress?
Following major systemic stress, the plasmacortisol increases to approximately 35-45 ug/dl
0
10
20
30
40
50
60
70
80
Base 45' Inc. 15' XC 1hCPB 2.5hCPB 4hCPB POD1 POD2
Co
rtis
ol
ug
/dl
Avg. Grp 1
Avg. Grp 2
Avg. Grp 3
Avg. Grp 4
Avg. Grp 5
Avg. Grp 6
0
5
10
15
20
25
30
35
40
45
0630 0730 0830 0930 1030 1130 1230 1330 1430 1530 1630 1730 1830
Baseline Post-LPS
Endotoxin
+ + + + + + *
Rassias et al, CCM 2005 Yeager et al, JCTA, 2005
Dose-Response 2010
Pre-treatment With Stress Cortisol Enhances the Human Systemic Inflammatory Response to Bacterial Endotoxin
Crit Care Med, In Press
What next?
Marked individual variability in GC-induced responses Large databases Cellular/molecular
mechanisms
IL-6 Control
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Dose-Response 2010