The role of IL-17A in postmenopausal inflammatory events, such as in osteoporosis 1 Ildikó Molnár,...
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Transcript of The role of IL-17A in postmenopausal inflammatory events, such as in osteoporosis 1 Ildikó Molnár,...
The role of IL-17A in postmenopausal inflammatory events,
such as in osteoporosis
1 Ildikó Molnár, MD, CSc, 2 Ilona Bohaty, MD, 1Éva Somogyiné-Vári1Immunoendocrinology and Osteoporosis Centre,
2Regional Centre of Hungarian National Blood Transfusion Service,
Debrecen, Hungary
Summit 2015, Houston
IL-17 cytokine
IL-17 (called as IL-17A) is characterized by:T-cell-derived cytokine secreted from Th17 cells, which are distributed from
other effector CD4+ T helper cells, such as Th1, Th2 and regulatory T (Treg) cells.
Sources of IL-17: Cells of innate and adaptive immunity (T and B cells, NK, NKT, γδ T cells, neutrophils, basophils, mast cells, monocyte-macrophages, dendritic cells). Epithelial, endothelial, vascular and stromal cells.
IL-17 initiated cytokine/chemokine productions: IL-6, TNFα, IL-1β, IL-8, CXC1, CXC2, CXC8, CCL2, MCP-1 Summit 2015, Houston
Arteriosclerosis(cardiovascular
diseases)
Increased IL-17 production-related diseases
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Local inflammation (cytokine interplay chemokine)
Autoimmunity
Allergy
Host defense mechanism(infection, transplantation)
Tissue repair
Bone loss(osteoporosis)
Immune dysfunction associated with estrogen deficiency
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Estrogen Estrogen deficiency
Th17 IL-17↑
spleen
neutrophilrecruitment
IL-6 secretion
T cell activation
peripheralmononuclear cells
osteoclastestrogen receptor
IL-1↑ TNFα ↑
osteoblast
TGFβ ↓ IFNγ ↑
IL-6 secretionBONE LOSS
RANK ligand ↑
Patients and methods
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Pre- (n=22, mean age 41 yr) and postmenopausal (n=72, mean age 65 yr) women were studied.Serum levels of IL-17A, IL-6, MCP-1 (macrophage-chemoattractant protein-1), sRANK (soluble receptor activator of NF-κB) ligand and OPG (osteoprotegerin) were measured by enzyme-linked immunosassay (ELISA).Serum levels of estradiol were measured by chemi-luminescence assay in fully automatized manner. Bone mineral density was detected by dual-energy X-ray absorptiometry (DXA) using Hologic Discoveryequipment.
We studied in pre- and postmenopausal women: The relationship among serum IL-17A levels, estrogen deficiency and postmenopausal period.
The relationships among serum IL-17A, sRANK ligand, OPG levels and bone mineral densities.
The relationship between vitamin D3 deficiency and serum IL-17A levels.
The relationship between serum IL-17A and IL-6 or MCP-1 levels.
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Synergism between bone loss and arteriosclerosis via IL-17 cytokine.
The relationship among serum IL-17A levels, estrogen deficiency
and postmenopausal period.
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Serum IL-17A levels were significantly higher in women with estrogen deficiency.
Figure 7
2,8
2,9
3
3,1
3,2
3,3
3,4
3,5Se
rum
IL-1
7A le
vels
(ng/
ml)
(mean ±SD) 3.01 3.43± 0.38 ± 0.56
P<0.001
patient groups
n=16 n=78
OR: 17.74 RR: 5.64CI95%: 3.52-79.62
estradiol 73.54±0.86 pmol/l
estradiol 304.66±234.33 pmol/l
estradiol levelsbelow 83 pmol/l
estradiol levelsin the normal range
0
1
2
3
4
Seru
m IL
-17A
leve
ls (n
g/m
l)
age-related groups
50-59 60-69 70-79 80-89n=20 n=34 n=10 n=8
ranges of age (years)
P<0.003
P<0.04
mean±SD 3.59 3.31 3.63 3.97±0.65 ±0.4 ±0.46 ±0.77
Summit 2015, Houston
Figure 8
Inreased serum IL-17A levels showed an age-related dependency in postmenopause.
Women with menopausal age > 10 years
Seru
m IL
-17A
lev
els
(ng/
ml) Y= 3.112 + (X*0.018)
p<0.049
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Correlation between serum IL-17A levels and the post-menopausal period of women aged 60 to 89 years.
Figure 9
3,1
3,15
3,2
3,25
3,3
3,35
3,4
3,45
3,5
3,55
3,6Se
rum
IL-1
7A le
vels
(ng/
ml)
(mean ±SD) 3.57 3.29± 0.59 ± 0.39
P<0.026
patient groups
n=54 n=18
Yes hysterectomy
No hysterectomy
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Figure 10
Inreased serum IL-17A levels showed a dependency on the history of hysterectomy in postmenopause.
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Inreased serum IL-17A levels showed a postmenopausal age-related dependency on the history of hysterectomy.
Figure 110
1
2
3
4
Seru
m IL
-17A
leve
ls (n
g/m
l)
age-related groups0-10 yr 11-20 yr 21-30 yr 31-40 yrn=17 n=3 n=20 n=5 n=14 n=7 n=3 n=3
menopausal age
mean±SD 3.54 3.49 3.46 3.25 3.62 3.13 4.3 3.55 ±0.68 ±0.6 ±0.47 ±0.26 ±0.46 ±0.28 ±1.09 ±0.56
P<0.008
Yes hysterectomy
No hysterectomy
Relationship between serum IL-17A levels and bone mineral densities (BMDs).
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Postmenopausal Premenopausal womenosteopenia osteoporosis normal in lumbar region
(-1>T-score>-2.5) (T-score<-2.5) (T-score >-1)n=31 n=41 n=22
2
2,5
3
3,5
4
4,5
5
Seru
m IL
-17A
leve
ls (n
g/m
l)
patient groups
(mean ±SD) 3.31 ± 0.08 3.65 ± 0.61 2.88 ± 0.08 ng/mlP<0.027
P<0.013 P<0.0001
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Figure 13
Increased serum IL-17A levels were associated with relevant bone loss in postmenopause compared to those in premenopause.
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Serum IL-17A levels were significantly higher in post-menopausal osteoporotic women in the lumbar and femoral total regions.
Figure 14
Fem
oral
nec
kbo
ne m
iner
al d
ensi
ty (g
/cm
2 )
Serum IL-17A levels (ng/ml)
Y=0.914 - (x*0.074)p<0.001
Fem
oral
bone
min
eral
den
sity
(g/c
m2 )
Serum IL-17A levels (ng/ml)
Y=1.122 - (x*0.086)p<0.003
Lum
bar
bone
min
eral
den
sity
(g/
cm2 )
Serum IL-17A levels (ng/ml)
Y=0.972 - (x*0.059)p<0.022
Summit 2015, HoustonFigure 15
Serum IL-17A levelscorrelated inversely with bone mineral densities in postmenopause.
Lu
mb
ar r
egio
nF
emor
al r
egio
ns
Relationship between serum IL-17A and sRANK ligand or
OPG levels.
Summit 2015, Houston
Premenopausal women, n=18.
Postmenopausal osteopenic women, n=31.osteoporotic women, n=41.
A
C
B
Seru
m IL
-17
leve
ls (n
g/m
l)
mean±SD 2.89±0.07 3.31±0.43 3.65±0.60
P<0.007
P<0.0001
P<0.0001
patient groups Seru
m s
RAN
K lig
and
leve
ls
(ng/
ml)
mean±SD 2.61±0.61 2.49±0.61 2.88±0.84
P<0.027
patient groups
Seru
m O
PG le
vels
(ng/
ml)
mean±SD 1.43±0.07 1.39±0.07 1.43±0.07
P<0.038
patient groups
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Figure 17
Increased serum IL-17A and sRANK ligand levels were detected in osteoporotic women.
IL-17A sRANK ligand
OPG
Serum sRANK ligand levels (ng/ml)
Seru
m IL
-17
leve
ls (n
g/m
l)
Y= 2.924 +(X*0.2)P<0.009
Ratio of serum sRANK ligand and OPG levels
Seru
m IL
-17
leve
ls (n
g/m
l)
Y= 2.971 + (X*0.26)P<0.023
Serum OPG levels (ng/ml)
Seru
m IL
-17
leve
ls (n
g/m
l)
Y= 1.294 + (X*1.55)NS
Summit 2015, Houston
Figure 18
Serum IL-17A levels correlated positively with sRANK ligand and did not with OPG serum levels, but with the ratio of sRANK ligand and OPG serum levels.
sRANK ligand OPG
Ratio of sRANK ligand and OPG
Vitamin D3 deficiency and serum IL-17A levels.
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ParametersVitamin D3deficiency
(n=18)<50 nmol/l
Vitamin D3insufficiency
(n=25)51-75 nmol/l
Vitamin D3sufficiency
(n=11)>75 nmol/l
P-values
Age(years)
59±17 61±13 61±12
BMI*(kg/m2)
29±5 29±6 29±6
Vitamin D3(nmol/l)
16,84±6,06 35,08±5,79 68,95±44
IL-17A(ng/ml)
13,35±2,9 o 12,07±2,61 11±1,9 o 0.033
MCP-1**(ng/ml)
17,35±2,9 16,62±2,07 16,18±1,23
IL-6(ng/ml)
26,11±12,66 26,25±12,23 22,68±13,52
Serum IL-17A levels were significantly higher in post-menopausal women with vitamin D3 deficiency.
*Body mass index (BMI) **Monocyte chemoattractant protein-1 (MCP-1)Summit 2015, Houston
Table 1
D3-
vita
min
seru
m le
vels
(nm
ol/l
)
IL-17A serum levels (ng/ml)
Y= 64,45-(X*2,34)P<0.026 r=0.3033
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Figure 20
Serum IL-17A levels correlated inversely with vitamin D3 serum levels in postmenopause.
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Relationship between serum IL-17A and IL-6 or MCP-1 levels.
IL-1
7A se
rum
leve
ls (n
g/m
l)
MCP-1 serum levels (ng/ml)
Y= (X*0,81)-1.43P<0.0001 r=0.6745
Summit 2015, Houston
Figure 22
Serum IL-17A levels correlated positively with serum MCP-1 levels in postmenopause.
IL-1
7A se
rum
leve
ls (n
g/m
l)
IL-6 serum levels (ng/ml)
Y= 8,47+(X*1,46)P<0.0001 r=0.6693
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Figure 23
Serum IL-17A levels correlated positively with serum IL-6 levels in postmenopause.
Summit 2015, Houston
Synergism between bone loss and arteriosclerosis via IL-17 cytokine.
bone loss
From Butcher M and Galkina EV , Thromb Haemost, 2011, 106(5): 787-795.
Figure 24
arteriosclerosis
Conclusions
Summit 2015, Houston
The high prevalence of increased serum IL-17A levels was connected to postmenopausal estrogen deficiency and showed a postmenopausal period-related dependency. Postmenopausal osteoporosis was associated with increased serum IL-17A and sRANK ligand levels, but only weakly increased serum OPG levels. Vitamin D3 deficiency was associated with higher serum IL-17A levels in postmenopause. The strong correlation between serum IL-17A and IL-6 or MCP-1 highlighted the relationship between osteoporosis and arteriosclerosis, as well as cardio- vascular diseases.
Thank youfor your attention!
Summit 2015, Houston
Participated in this work:Regional Centre of Hungarian National Blood Transfusion Service, Debrecen, Hungary
Ilona Bohaty MD
EndoMed, Immunoendocrinology and Osteoporosis Centre
Éva Somogyiné-Vári