ARTICLE
Auteur(s) : Kaiming Zhang1, Ruifeng
Liu1, Guohua
Yin1, Xinhua Li1, Junqin Li1,
Jing Zhang2
1Institute of Dermatology, Taiyuan City Centre
Hospital, Affiliated to Shanxi Medical University, No.1 Dong
San Dao Xiang, Taiyuan, Shanxi Province 030009, China
2Internal Medicine Department, Taiyuan City Centre
Hospital, Affiliated to Shanxi Medical University, Taiyuan,
Shanxi Province 030009, China
accepté le 20 Août 2009
Psoriasis is a chronic inflammatory skin disorder with
characteristics such as hyperproliferation of basal keratinocytes,
a thickened and scaly epidermis, and recruitment of inflammatory
cells to the skin [1, 2]. While its pathogenesis has been primarily
attributed to various factors including environmental factors [3,
4], immune abnormalities [5, 6], as well as genetic inheritance [2,
7, 8], the exact mechanisms are still largely unknown. As an
autoimmune disease, psoriasis is associated with a host of immune
abnormalities [5, 9] and is believed to be induced by a
dysregulated interplay between keratinocytes and infiltrating
immune cells [10].
Several lines of evidence have suggested an involvement of
hematopoiesis in psoriasis. Firstly, almost all the types of
immunocytes differentiated from bone marrow hematopoietic stem
cells are involved in the immunopathology of psoriasis [5, 11-13].
Secondly, decreased colony formation, proliferative capacity of
hematopoietic stem cells and hyper-proliferation of monocytic
lineages have been reported in patients with psoriasis [14, 15].
Thirdly, T cells differentiated from psoriatic hematopoietic cells
are functionally deficient in response to polyclonal streptococcal
superantigens and in suppressing effector T cells [14]. Finally,
and perhaps most importantly, psoriatic lesions can be healed when
patients receive a hematopoietic stem cell transplant from a
non-psoriatic donor, and non-psoriatic patients receiving bone
marrow from a donor with psoriasis can develop the disease [16,
17].
Differentiation of hematopoietic cells is a process of
hematopoiesis controlled by their microenvironment [18] consisting
of hematopoietic stem and progenitor cells and their progenies, in
close contact with a connective tissue network of bone marrow
stromal cells (BMSCs), from which secreted cytokines regulate
proliferation and differentiation of hematopoietic stem cells.
However, whether cytokine secretion from BMSCs is aberrant in
psoriasis has not been evaluated. In the present study, we
characterized BMSCs isolated from patients with psoriasis, and
compared their cytokine production with those from healthy
volunteers. We demonstrated differential secretion profiles of
cytokines in BMSCs between those two groups, suggesting that the
hematopoietic microenvironment is involved in the pathogenesis of
psoriasis.
Material and methods
Subjects
24 outpatients (8 females and 16 males, aged from
16 to 59 with mean age at 30.38 ± 13.72) at the Institute
of Dermatology, Taiyuan City Centre Hospital, Affiliated to Shanxi
Medical University, and 20 volunteers with the same sex and
age combination as the patients were enrolled in this study. The
volunteers showed no systemic diseases in a routine health
examination. These patients were diagnosed with psoriasis vulgaris
based on both the appearance of the skin and the lesional shave
skin biopsy, and had 7 day to 20 year courses of the
diseases with 10%~80% plaque coverage.
The psoriasis was scored based on the Psoriasis Area and
Severity Index (PASI), which measures the average redness,
thickness, and scaliness of the lesions (each graded on a
0-4 scale), weighted by the area of involvement (head and
neck, trunk, upper and lower extremities). All patients had scores
between 0.1-12 with an average score of 5.05 ± 3.33. Among
them, eight patients were in the progressive spread stage of
psoriasis and fourteen patients were in a stationary stage. No
subjects took cortex steroid hormones, tretinoin,
immunosuppressants or phototherapy within two months of enrollment.
All of the patients and volunteers were informed about the aims of
the study and gave their informed consents. The protocol involving
human subjects was approved by the Medical Ethics Committee of
Taiyuan City Centre Hospital.
Reagents
Low glucose DMEM medium, fetal bovine serum (FBS) and Percoll were
from Invitrogen. Mouse monoclonal antibodies directed against human
stem cell factor (SCF), granulocyte colony stimulating factor
(G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF),
interleukin-6 (IL-6), interleukin-1α (IL-1α),
interleukin-1 β(IL-1β), interleukin-3 (IL-3),
interleukin-7 (IL-7), interleukin-8 (IL-8),
interleukin-11 (IL-11), epidermal growth factor (EGF),
vascular endothelial growth factor (VEGF), tumor necrosis factor-α
(TNF-α), leukemia inhibitor factor (LIF), hepatocyte growth factor
(HGF), platelet-derived growth factor (PDGF), and HRP-labeled
rabbit antibody against mouse IgG were from Abcam. Phycoerythrin
(PE) or fluorescein isothiocyanate (FITC)-labeled mouse antibodies
directed against human CD29, CD34, CD45, and HLA-DR were from BD
Sciences. Microplate reader Labsystems 352 and Flow Cytometer
FACSCalibur were from Finland and BD USA, respectively.
Isolation of bone marrow stromal cells (BMSCs)
Human BMSCs were grown from aspirates taken from the posterior
superior iliac spine of the patients with psoriasis and healthy
volunteers. 5 mL heparinized aspirates were diluted
1:2 with low glucose DMEM and centrifuged through a percoll
density gradient for 30 min at 2,000 rpm. The mononuclear
cells at the interface were collected, washed with low glucose DMEM
twice, resuspended at a concentration of 1 × 106/mL in
complete medium (low glucose DMEM supplemented with 10% FBS,
100 U/mL penicillin, 100 μg/mL streptomycin), and plated
at 1 × 106/well in 24-well plates. The cells were then
incubated at 37 °C in a humidified atmosphere supplemented
with 5% CO2 and 2 days later, the nonadherent cells
were removed by replacing the medium. Later on, medium was changed
by half every 4 days. At 90% confluency, the cells were
detached by incubation with 0.25% trypsin, diluted 1:2 or
1:3 with complete medium, and then replated at 1 ×
105/well in 24 well plates.
Identification of cell purity and collection
of cell medium
Cells at passage 3 and their culture supernatants were
collected from each well of 20 wells. Culture supernatants
were stored in sterile tubes at – 20 °C after filtering
with a 0.45 μm filter for further ELASA analysis to determine
the content of cytokines. Cells detached with 0.02% EDTA were
washed and resuspended with phosphate-buffered saline. 2 ×
105 cells were transferred into a tube and incubated in
the dark with phycoerythrin (PE) labeled mouse antibodies directed
against the cell surface markers human CD34 and fluorescein
isothiocyanate (FITC) labeled mouse antibodies directed against the
cell surface markers human CD45, for 30 minutes. Another 2 ×
105 cells were incubated in the dark with PE labeled
monoclonal antibody directed against CD29 and FITC labeled
monoclonal antibody directed against HLA-DR for 30 minutes.
After washing with PBS, the cells were subjected to two-color flow
cytometric analysis to examine the proportion of positive cells.
Quantification of cytokines in medium
The contents of cytokines were measured based on direct
enzyme-linked immunosorbent assay (ELISA). The 96-well plate was
coated overnight at 4 °C with 50 μL medium/well from
psoriatic and normal BMSCs, respectively. After plate washing,
200 μL/well 0.25% gelatin was added and the plate was
incubated for 2h at RT. 50 μL of primary antibody diluted by
1:100 was introduced into the wells and incubated for 1h at
RT. After rinsing out the excessive primary antibody, 50 μL of
the HRP-labeled secondary antibody was added to the wells and
incubated for 45 min at 37 °C. Finally, after rinsing out
excessive labeled antibody, HRP enzyme activities were determined
by an o-phenylenediamine dihydrochloride (OPD) reaction, which was
terminated by adding 1M H2SO4 after
10 minutes’ incubation at RT. The concentration of each
cytokine measured was calculated by CurveExpert 1.3 software.
Statistical analysis
Data were expressed as mean ± standard deviation of mean. The
independent sample t-test was used to compare the mean values of
samples from patients with psoriasis and healthy volunteers, using
SPSS13.0 software (SPSS Inc, Chicago, IL). Pearson analysis
was used to evaluate the correlation of cytokine secretion with
psoriasis severity. A p less than 0.05 was considered to
be statistically significant.
Results
Cellular morphology of psoriatic and normal
BMSCs
Isolated BMSCs from both psoriasis patients and healthy volunteers
showed no differences under microscopy. Cells attached to the
bottom of the plates after 24 h incubation. At day 7 to
10, cells showed obvious enlargement and proliferation forming
small colonies with several to tens of fusocellular, triangular,
polygonal cells, sporadically. Cells displayed a typical fibroblast
morphology with multi-layered flat cell bodies with short cell
processes connected to the adjacent cells. At day 14, cells reached
confluence. When treated with trypsin, the cells became round
shaped and after reattaching to the plate and incubating for
24 h, the cell morphology reverted to the primary BMSC shape
and reached confluence after incubating for 4~5 days.
Analyses for cell surface marker antigens
of psoriatic and normal BMSCs
The cell surface marker profiles in adherent psoriatic and normal
BMSCs were detected by flow cytometry analysis. Cells were
incubated with either phycoerythrin (PE) or fluorescein
isothiocyanate (FITC)-labeled mouse antibodies, directed against
the cell surface markers human CD29, CD34, CD45 and human
leukocyte antigen (HLA)-DR, respectively. Then the cells were
subjected to a flow cytometry analysis to examine the proportion of
positive cells. 90% of both psoriatic and normal BMSCs showed
positive to CD29 and negative to CD34, CD45 and HLA-DR,
in concordance with antigenic profiles of BMSCs reported previously
(figure 1).
Differential secretion of cytokines from psoriatic
and normal BMSCs
Table 1 shows the content of cytokines
in the culture medium secreted from psoriatic and normal BMSCs,
measured by direct ELISA as described in Materials and Methods
Section. Among the inflammatory cytokines, the concentrations of
SCF and G-CSF secreted from psoriatic BMSCs were significantly
higher than those from normal BMSCs (74.15 ± 15.50 pg/mL vs 54.18 ±
11.87 pg/mL for SCF, P = 0.001 and 55.55 ± 15.65 pg/mL vs 40.42 ±
5.14 pg/mL for G-CSF, P < 0.001, respectively). By contrast, the
concentrations of IL-1α and IL-1β secreted from psoriatic BMSCs
were significantly lower than those from normal BMSCs (119.02 ±
35.58 pg/mL vs 327.20 ± 115.56 pg/mL, P < 0.001 and 73.17 ±
29.98 pg/mL vs 117.83 ± 54.44 pg/mL, P = 0.032, respectively). The
concentrations of GM-CSF and IL-11 secreted from psoriatic BMSCs
showed no significant differences from those of normal BMSCs
(171.28 ± 41.04 pg/mL vs 162.64 ± 36.75 pg/mL and 116.69 ± 28.49
pg/mL vs 130.63 ± 14.53 pg/mL, respectively, p > 0.05). Among
the hematopoietic cytokines, only the concentration of IL-6
secreted from psoriatic BMSCs was significantly higher than that
from normal BMSCs (85.97 ± 20.45 pg/mL vs 59.35 ± 16.22 pg/mL, P =
0.001), while others including IL-3, IL-8, EGF, VEGF, TNF-α, LIF,
HGF, PDGF secreted from psoriatic BMSCs showed significant
decreases compared with those from normal BMSCs (P < 0.05). The
concentrations of IL-7 secreted were not different between the two
groups (P > 0.05).
Table 1 Content of cytokines in the culture medium of
BMSCs from psoriasis and control group (pg/mL)
|
Group
|
|
|
|
Cytokines
|
Psoriasis
|
Control
|
T-value
|
P-value
|
|
Inflammatory cytokines
|
|
IL-1α
|
119.02 ± 35.58
|
327.20 ± 115.56
|
– 5.588
|
< 0.001**
|
|
IL-1β
|
73.17 ± 29.98
|
117.83 ± 54.44
|
– 2.444
|
0.032*
|
|
SCF
|
74.15 ± 15.50
|
54.18 ± 11.87
|
3.641
|
0.001**
|
|
G-CSF
|
55.55 ± 15.65
|
40.42 ± 5.14
|
4.224
|
< 0.001**
|
|
GM-CSF
|
171.28 ± 41.04
|
162.64 ± 36.75
|
0.575
|
0.569
|
|
IL-11
|
116.69 ± 28.49
|
130.63 ± 14.53
|
– 1.881
|
0.070
|
|
IL-3
|
236.19 ± 35.34
|
530.87 ± 335.23
|
– 2.773
|
0.021*
|
|
IL-6
|
85.97 ± 20.45
|
59.35 ± 16.22
|
3.654
|
0.001**
|
|
IL-8
|
55.87 ± 9.95
|
252.07 ± 120.23
|
– 5.153
|
0.001**
|
|
Hematopoietic cytokines
|
|
EGF
|
48.25 ± 13.34
|
65.29 ± 8.16
|
– 3.737
|
0.001**
|
|
VEGF
|
93.53 ± 28.03
|
305.81 ± 109.11
|
– 6.069
|
< 0.001**
|
|
TNF-α
|
21.48 ± 1.15
|
31.40 ± 8.47
|
– 3.691
|
0.005**
|
|
LIF
|
44.77 ± 11.50
|
56.98 ± 14.26
|
– 2.629
|
0.013*
|
|
HGF
|
58.83 ± 9.20
|
424.55 ± 249.43
|
– 4.635
|
0.001**
|
|
PDGF
|
49.38 ± 11.94
|
119.06 ± 79.92
|
– 2.744
|
0.022*
|
|
IL-7
|
94.38 ± 28.52
|
92.25 ± 16.89
|
0.219
|
0.828
|
The correlation of cytokine secretion from psoriatic BMSCs
with psoriatic severity
Pearson analyses indicated that the levels of SCF, G-CSF, IL-6,
IL-1α, IL-1β, IL-3, IL-8, EGF, VEGF, TNF-α, LIF, HGF, PDGF, GM-CSF,
IL-11 and IL-7 were not related to psoriatic severity,
evaluated with PASI (p > 0.05).
Discussion
The expression levels of various cytokines in the skin and serum,
such as interleukins (IL-1, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18,
IL-19, IL-20, IL-22, and IL-23), interferon-gamma (IFN-γ) and tumor
necrosis factor-alpha (TNF-α) have been reported in the literature
[19, 20]. They appear to regulate the infiltration of immunocytes
and the proliferation of keratinocytes in psoriatic lesions. In the
present study, by comparing the levels of cytokines secreted in
vitro by cultured bone marrow stromal cells isolated from psoriatic
patients with those from healthy volunteers, our results showed
differential profiles of cytokine secretion in these two groups.
Secretions of SCF, IL-6 and G-CSF are upregulated and
secretions of IL-1α, IL-1β, IL-3, IL-8, EGF, VEGF, TNF-α, LIF, HGF,
PDGF are down-regulated in psoriatic BMSCs compared with their
counterparts in normal BMSCs (p < 0.05). The levels of cytokines
secreted from psoriatic BMSCs were not related to psoriatic
severity evaluated with PASI, indicating that the abnormality of
cytokine secretion is due to the abnormality of BMSCs themselves
other than the inflammatory reaction of the body. Abnormality of
BMSCs has been related to a decreased secretion of cytokines in
other dermatological diseases, such as systemic lupus erythematosus
[21]. Cytokines secreted from BMSCs have profound influences on the
differentiation of hematopoietic cells as well as on the
proliferation of bone marrow stem cells themselves. Therefore, they
may have broader effects than those expressed in keratinocytes, and
may be involved in all three phases of the pathogenesis of
psoriasis recently proposed by Sabat [22] et al. Obviously,
most cytokines are multifunctional factors [9, 18, 23-34]. While
IL-1 (IL-1α and β), SCF, G-CSF, GM-CSF are traditionally considered
as pro-inflammatory cytokines, they are shown to be involved in the
proliferation and colonization of marrow hematopoietic progenitor
cells, and the apoptosis and differentiation of hematopoietic stem
cells [23, 32, 35-37]. IL-3, IL-6, LIF, HGF and PDGF are
pro-hematopoietic factors secreted from BMSCs, and TNF α is an
anti-hematopoietic factor. The balance between those pro- and anti-
hematopoietic factors is a key for hematopoietic homeostasis. The
aberrant secretion of cytokines in psoriatic patients is likely to
result in an abnormal immune differentiation and activity, even the
proliferation of the stem cells themselves. We have previously
demonstrated that hematopoietic cells are involved in psoriasis
[1]. In the present paper, we presented novel evidence that the
hematopoietic microenvironment is also involved in psoriasis,
presumably by regulating the process of hematopoiesis. Thus, the
psoriasis can be considered as an inflammatory, immunocyte-mediated
skin disease with an aberrant hematopoietic microenvironment of the
bone marrow, although the causes are not clear yet. In this
autoimmune disease, the hematopoietic microenvironment may be
changed as the result of adapted immune responses, but these are
more likely to be innate effects. Most convincingly, psoriatic
patient recipients of healthy bone marrow achieve a long-term
remission or amelioration of the disease [38]. Conversely, healthy
recipients without a family history of psoriasis receiving
psoriatic bone marrow, developed psoriasis later in life [16].
Taken together, this link of psoriasis with aberrant hematopoietic
microenvironment suggests a potential psoriatic pathogenesis.
Acknowlegements
This work is supported by the National Natural Science Foundation
of China (NFSC 30771940). Conflict of interest: none.
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