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L E W I S H . K U L L E R , M D , D R P H

P R O F E S S O R E M E R I T U S

T H U R S D A Y , M A Y 7 , 2 0 1 5

To Cytokine or Not to Cytokine

1

(2)

Definition of Cytokine

Taber’s Cyclopedic Medical Dictionary, 22nd ed, 2013

2

(3)

The acute phase response is the name

given to a characteristic pattern of

alterations in the concentrations of

plasma proteins that occurs following

a wide variety of different forms of

inflammation.

Kuller LH et al. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Am J Epidemiol 1996;144:537-47

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WHI Talk 5-2015

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Cytokines are Produced by Several Inflammatory and Vascular Cells

IL-12 and IL-18, produced by

macrophages (Mac), are

potent inducers of IFN-γ and

promote the differentiation of

naïve T cells into

proatherogenic Th1 cells.

Macrophage-derived cytokines

activate SMC and EC to

produce an array of

proinflammatory mediators.

On the other hand, the

antiinflammatory cytokines

IL-10 and TGF-β, also

produced by macrophages,

promote antiatherogenic Treg

cell differentiation. Other

antiinflammatory mediators

with potent antiatherogenic

properties include 33,

IL-1ra, and IL-18 binding protein

(IL-18BP). In naive CD4+ T

cells from mice, Th17 cells are

induced in response to a

combination of IL-6 or IL-21

and TGF-β and require

induction of the transcription

factor RORγt. In human (h),

Th17 differentiation requires

TGF-β, IL-1β, and IL-6.

(5)

Psaty B et al.

5

(6)

Characteristics of Innate and Adaptive Immune

Responses

Weyand CM et al. T-cell immunity in acute coronary syndromes. Mayo Clin Proc 2001;76:1011-20

6

(7)

Feedforward Loop Between Innate and Adaptive

Immune Systems in Systemic Autoimmunity

Factors of the innate system activate

and promote adaptive components,

which feedback into the innate arm

to promote immune activation.

Central components of the innate

system that feed into the adaptive

system in systemic autoimmune

diseases include type 1 interferon

and other cytokines, MHC II, and

apoptotic debris, while important

factors from the adaptive system

promoting innate responses

encompass proinflammatory

cytokines, autoantibodies, and

immune complexes. BAFF=B-cell

activating factor (TNFSF13B).

IFNα=interferon α. IL=interleukin.

LTα= lymphotoxin α. TGF

β=transforming growth factor β.

TNFα=tumour necrosis factor α.

Wahren M et al. Autoimmune rheumatic diseases 3. Immunopathogenic mechanisms of systemic autoimmune disease. Lancet 2013;382:819-31

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WHI Talk 5-2015

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Pathophysiologic Relevance of Cytokines in

Chronic Liver Disease

Most types of cells in the liver, including

Kupffer cells, hepatocytes, and stellate

cells, either synthesize or respond to

cytokines. In the early phase of chronic

liver disease, specific agents such as

viruses, ethanol, and toxins may stimulate

the production of cytokines. In the late

phase, endotoxin may be the key agent

stimulating cytokine production. Clinical

features of chronic liver disease that are

mediated by cytokines include cachexia,

cholestasis, fibrosis, synthesis of

acute-phase proteins, and

hypergammaglobulinemia. Whereas

proinflammatory cytokines such as tumor

necrosis factor α (TNF-α) and

interleukin-6 are mainly involved in cholestasis and

the synthesis of acute-phase proteins,

transforming growth factor β (TGF-β)

released by activated Kupffer cells and

hepatocytes may be one of the critical

cytokines involved in fibrosis. In patients

with progressive liver disease, the balance

between proinflammatory and

antiinflammatory cytokines may be

shifted toward the proinflammatory axis,

thus the counteracting antiinflammatory

cytokines are unable to control

inflammation and fibrosis.

Tilg H, et al. Cytokines in alcoholic and nonalcholic steatohepatitis. N Engl J Med 2000;343:1467-76

9

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Wong E et al. Epidemiology of cytokines. The Women On the Move through Activity and Nutrition (WOMAN) Study. Am J Epidemiol 2008;168:443-53

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WHI Talk 5-2015

Changes in IL-1a, IL-6, CRP by Weight Loss

Categories

(11)

WHI Talk 5-2015

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Number of Split Samples Above 25% Difference by

Cytokine (WHI BA20 RA Study), N=153

Cytokine

N

%

IL-1B

33

21

IL-2

60

39

IL-4

68

44

IL-5

37

18

IL-6

30

20

IL-7

23

15

IL-8

23

15

IL-10

32

20

IL-12

41

26

IL-13

40

26

IL-17

67

44

IL-18

33

22

TNF-a

51

33

MIP-18

17

11

G-CSF

42

27

MCP-1

26

17

GM-CSF

12

8

12

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WHI Talk 5-2015

The CVs for 40 blinded duplicates, 20

placed within the same batch, and 20

placed across different batches.

Results are shown separately for 67

Bio-Rad markers (A–C) and 97

Millipore markers (D–F) across 3

specimen types–heparin plasma,

serum, and EDTA plasma.(D–F)

across 3 specimen types—serum,

heparin plasma, and EDTA plasma.

Chaturvedi AK et al. Evaluation of multiplexed cytokine and inflammation marker measurements: a methodologic study. Cancer Epidemiol Biomarkers Prevention 2011;20:1902-11

(14)

Median Values of Cytokines by RA+/-

Cytokine (pg/mL)

Likely RA Neg

(n=2135)

Likely RA (n=742)

P value

IL1B

1.53

1.92

<0.0001

IL2

3.31

6.18

<0.0001

IL4

1.61

2.00

<0.0001

IL5

3.03

3.57

<0.0001

IL6

6.13

9.30

<0.0001

IL7

6.91

7.82

<0.0001

IL8

8.49

9.36

<0.0001

IL10

2.41

2.76

<0.0001

IL12

12.7

16.9

<0.0001

IL13

2.44

3.21

<0.0001

IL17

0.35

2.85

<0.0001

GCSF

146.8

159.0

0.0005

MCP_1

14.5

18.4

<0.0001

MIP_1B

41.9

45.1

0.0014

IFN-Y

42.1

55.1

<0.0001

Birru, et al. WHI BA20 RA ms proposal. Associations of HLA-DR Shared Epitope Alleles and Serum Cytokines Among Postmenopausal women with and without

(15)

Comparison of Extremes of IL6 (1Q vs. 4Q) Among

anti-CCP+ or DMARD+ at Baseline (WHI BA20 RA Study)

IL6 1Q

IL6 4Q

P

value

N

%

N

%

BMI

≤25

53

43.1

70

56.9

0.109

25.1-30

62

56.4

48

43.6

30.1-35

29

46.0

34

54.0

>35

25

59.5

17

40.5

Smoking

Never

79

56.8

60

43.2

0.028

Ever

89

44.7

110

55.3

Joint Pain

Not severe

138

53.9

118

46.1

0.014

Severe

31

38.3

50

61.7

Health

Good/excellen

t

134

55.4

108

44.6

0.004

Fair/poor

36

37.9

59

62.1

15

WHI Talk 5-2015

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Comparison of Extremes of IL6 (1Q vs. 4Q) Among

anti-CCP+ or DMARD+ at Baseline (WHI BA20 RA Study)

IL6 1Q

IL6 4Q

P value

N

%

N

%

anti-CCP

-

72

86.8

11

13.3

<.0001

+

98

38.1

159

61.9

RF

-

97

91.5

9

8.5

<.0001

+

73

31.2

161

68.8

Age

≤60

73

56.2

57

43.9

0.015

61-69

72

51.8

67

48.2

>69

25

35.2

46

64.8

# of shared epitopes

0

89

64.5

49

35.5

<.0001

1

66

46.2

77

53.9

2

9

19.6

37

80.4

16

WHI Talk 5-2015

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Cytokines by CHD Case – Control Among Anti-CCP+

Participants (WHI BA20 RA Study)

Cytokines (pg/mL)

No CHD

Median

CHD

Median

P-value

IL-1B

2.32

2.18

0.956

IL-2

10.00

11.06

0.480

IL-4

3.21

2.45

0.362

IL-5

4.42

4.26

0.997

IL-6

15.35

13.43

0.626

IL-7

9.25

9.24

0.610

IL-8

11.08

11.05

0.814

IL-10

3.03

3.02

0.862

IL-12

20.84

24.65

0.269

IL-13

4.13

3.91

0.704

G-CSF

180.09

178.03

0.847

MCP-1

19.70

18.76

0.991

MIP-1

40.84

44.99

0.752

TNF-a

39.08

35.26

0.976

IFH-g

71.31

66.53

0.884

IL-17

4.45

4.25

0.901

Kuller LH et al. WHI Rheumatoid Arthritis BA20 data

17

(18)

Cytokine

(pg/mL)

Alive at 2009

(n=461)

Deceased by 2009

(n=78)

Median

25

th

Percentile

75

th

Percentile

Median

25

th

Percentile

75

th

Percentile

P-value

IL-1B

2.0

1.3

3.8

2.5

1.6

6.6

0.070

IL-2

7.6

3.3

27.7

11.0

4.4

47.6

0.076

IL-4

2.0

1.1

3.2

2.2

1.5

3.6

0.185

IL-5

3.6

2.6

5.2

3.9

3.0

5.5

0.266

IL-6

11.0

6.2

25.5

13.0

8.4

49.5

0.028

IL-7

7.8

5.6

11.2

8.1

6.3

11.2

0.310

IL-8

9.4

6.9

12.2

9.6

8.0

13.3

0.034

IL-10

2.9

2.1

4.2

3.2

2.4

5.4

0.045

IL-12

17.8

10.9

36.2

22.2

14.9

66.9

0.015

Cytokines by Alive vs Dead for Anti-CCP+ Rheumatoid Arthritis

Participants (Excluding Women with Baseline CVD or Cancer)

Kuller LH et al. WHI Rheumatoid Arthritis BA20 data

(19)

Median

a

Cytokine Levels at Baseline by Anti-CCP and RF

Status Among Participants in the WHI RA Study

1.6

6.3

2.5

0.8

5.5

2.4 15.2 3.2 4.2 6.2

0

2

4

6

8

10

12

14

16

IL-1b*

IL-6*

IL-10

IL-17

WBC

Count

Med

ia

n

C

yt

oki

ne

Lev

el

p

g/

m

L

RF- (n=157)

RF+ (n-613)

Anti-CCP+ (n=770)

b

1.5

6.1

2.4

0.4

5.8

1.8

7.5

2.7

2.3

5.37

IL-1b*

IL-6*

IL-10

IL-17

WBC

Count

RF- (n=1912)

RF+ (n=302)

Anti-CCP- (n=2214)

c

Kuller LH, et al. Am J Epidemiol 2014;179:917-26

*p=<.01

a Wilcoxon test of median values. bInformation on RF status was missing for 2 women; information on

cytokine levels was missing for 2 women. cInformation on RF status was missing for 2 women; information on

cytokine levels was missing for 3 women.

19

(20)

1.06

1.73

2.31

2.49

1.04

1.24

1

1.53

1.17

1.56

1.05

2.77

1.23

1.14

1.12

2.09

0

0.5

1

1.5

2

2.5

3

RF+

IL6*

RF+

IL6*

RF+

IL6*

RF+

IL6*

CHD

Death

*4Q (vs IL6 1Q)

Anti-CCP+ or

DMARD+

Anti-CCP+

Anti-CCP- and

DMARD-

Anti-CCP- and

DMARD+

Cox Model, Covariate = Age, excluding RA at FU only or CVD at BL

Ag

e-A

dj

ust

ed HR

(21)

6.51

4.1

8.86

4.23

0

1

2

3

4

5

6

7

8

9

10

Q1

Q2

Q3

Q4

W

ei

gh

te

d

A

ge

-A

d

jus

te

d

Ra

te

/

1000 p

er

so

n

-yea

rs

Anti-CCP-/Baseline DMARD-

CHD Event by IL-6 excluding those with RA at

follow up only and those with CVD at baseline

N=1718 # of events 109 N=1478 # of events 78 N=1288 # of events 123 N=605 # of events 31

21

WHI Talk 5-2015

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Journal of Thrombosis and Haemostasis;

Volume 12, Issue 9,

pages 1391-1400, 23 JUL 2014 DOI: 10.1111/jth.12646

http://onlinelibrary.wiley.com/doi/10.1111/jth.12646/full#jth12646-fig-0002

Schematic mechanism of platelet and clotting activation elicited by

bacteria in pneumonia. The dotted lines indicate inhibition; the solid

lines indicate activation

22

(23)

Risk of Death Associated with Biomarker Levels

at Study Entry

Biomarker

Analysis

Type of

<25

th

Percentile

(Ref)

25

th

-49

th

Percentile

50

th

-74

th

Percentile

≥75

th

Percentile

OR associated with

One IQR Higher

Biomarker Level

after Log10

Transformation

OR

(95% CI)

P-

value

OR

(95% CI)

P-

value

OR

(95% CI)

P-value

OR

(95% CI)

P-value

hsCRP

(µg/ml)

No.

a

Adjusted

16/45

1.0 (ref.)

9/42

0.6 (0.2-1.5)

0.50

20/28

2.5 (0.9-7.2)

0.08

40/55

3.1 (1.2-8.0)

0.02

2.3 (1.4-3.7)

0.001

IL-6

(pg/ml)

No.

Adjusted

8/48

1.0 (ref.)

10/41

1.0 (0.3-3.6)

0.98

26/48

4.5 (1.4-14.2)

0.01

40/29

12.4 (3.6-42.0)

<0.0001

4.1 (2.3-7.3)

<0.0001

D-dimer

(µg/ml)

No.

Adjusted

8/51

1.0 (ref.)

22/54

8.3 (1.9-36.8)

0.005

18/40

12.6

(2.4-65.1)

0.003

37/25

41.2 (7.5-225.6)

<0.0001

5.3 (2.6-10.9)

<0.0001

Kuller LH et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 2008;5:e203

23

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Relationship Between Plasma Interleukin-6 Levels by Genotype in Groups Stratified

by (a) Demographics, (b) Presence of Metabolic Abnormalities, and (c) Lifestyle

Parameters

Jiang CQ et al. Interleukin-6 receptor gene polymorphism modulates interleukin-6 levels and the metabolic syndrome: GBCS-CVD. Obesity 2010;18:1969-74

24

(25)

Alterations of the T-cell repertoire during chronological aging

Vallejo AN. Immune remodeling: lessons from repertoire alterations during chronological aging and in immune-mediated disease. Trends Mol Med 2007;13:94-102

Thymic involution with age impairs production of new naïve T cells. Exposure to antigens throughout life results in the reduction of the size of the naïve reserve and the expansion of the memory compartment. Clonal expansion of memory cells along with antigen-independent homeostatic expansion help to maintain the number of circulating T cells. The rate of homeostatic expansion of naïve T cells increases late in life as a compensatory mechanism for the overall depletion of the naïve compartment. Clonal expansion of memory cells and homeostatic expansion of both naïve and memory cells cause telomere erosion that shortens the proliferative lifespan of T cells. Expansion of the memory compartment involves accumulation of oligoclonal T cells rather than the maintenance of overall TCR-repertoire

diversity. As depicted, 65 years is arbitrarily set to demarcate ‘young’ and ‘old’ age categories, and is seemingly the age at which slopes of telomere length and thymic output are minimal.

25

(26)

Age- and Sex-Standardized Prevalence of Individual

Infections

Zajacova A et al. Socioeconomic and race/ethnic patterns in persistent infection burden among U.S. adults. J Gerontol A Biol Sci Med Sci 2009;64A:272-9

26

(27)

Changes in TREC+ cells with age

Nasi M et al. Thymic output and functionality of the IL-7/IL-7 receptor system in centenarians: implications for the neolymphogenesis at the limit of human life. Aging Cell 2006;5:167-75

The percentage of sj-TREC

positive cells undergoes a

dramatic age-dependent

decline from young to

middle-aged subjects and

centenarians. Kruskal–

Wallis test among the

three groups revealed

a P < 0.0001. No

significant difference was

observed between young

and middle-aged donors.

Note that only the values

from individuals with

detectable TREC levels (all

young subjects, 10 out of

13 middle-aged donors, 4

out of 25 centenarians)

are shown here.

27

(28)

McElhaney JE, et al. Immunosenescence: what does it mean to health outcomes in older adults? Curr Opin Immunol 2009;21:418-24

28

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Schematic diagram for the cardiovascular

inflammation reduction trial (CIRT)

Ridker PM. Testing the inflammatory hypothesis of atherothrombosis: scientific rationale for the cardiovascular inflammation reduction trial (CIRT). J Thromb Haemost 2009;7(Suppl1):332-9

29

(30)

Balancing the IL-1β system and its contributions to human disease. MWS

indicates Muckle-Wells syndrome; NOMID, neonatal-onset multisystem

inflammatory disease

Ridker PM et al. Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: Rationale and design of the canakinumab anti-inflammatory thrombosis outcomes study (CANTOS). Am Heart J 2011;162:597-605

30

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Ridker PM et al. Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: Rationale and design of the canakinumab anti-inflammatory thrombosis outcomes study (CANTOS). Am Heart J 2011;162:597-605

31

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Activation of T cells requires two signals

T cell activation occurs only after interaction between T cell receptor (TCR) and antigen in the

context of MHC (signal 1) plus CD28 costimulation (signal 2).

References

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