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

Selye: Systemic Injury ResponseFrom Stress ©1950

Time

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 ActionsMunck, Guyre, Holbrook, 1984Dose-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

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

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

Dose-Response 2010

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

Dose-Response 2010

Selye: Systemic Injury ResponseFrom Stress ©1950

Time

Dose-Response 2010

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

Endotoxin Model of SIRS

Suffredini et al

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

Dose-Response 2010

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

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

0

500

1000

1500

2000

2500

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3500

4000

4500

Pre 2h 3h 4h 8h

Series1

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Series11

IL-6 Stress

0

500

1000

1500

2000

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4000

4500

Pre 2h 3h 4h 8h

Series1

Series2

Series3

Series4

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Dose-Response 2010