Interleukin (IL)-22, IL-17, IL-23, IL-8, vascular endothelial growth factor and tumour necrosis...

PHOTOBIOLOGY

BJD

British Journal of Dermatology

Interleukin (IL)-22, IL-17, IL-23, IL-8, vascular endothelialgrowth factor and tumour necrosis factor-a levels inpatients with psoriasis before, during and afterpsoralen–ultraviolet A and narrowband ultraviolet BtherapyS. Coimbra,*�� H. Oliveira,§ F. Reis,– L. Belo,*� S. Rocha,*� A. Quintanilha,�** A. Figueiredo,§ F. Teixeira,–E. Castro,*� P. Rocha-Pereira�,�� and A. Santos-Silva*�

*Servico de Bioquımica, Faculdade de Farmacia, Universidade do Porto, 4050-047 Porto, Portugal

�Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal

�Centro de Investigacao das Tecnologias da Saude, Instituto Politecnico da Saude Norte, CESPU, Gandra-Paredes, Portugal

§Servico de Dermatologia, Hospitais da Universidade de Coimbra, Coimbra, Portugal

–Faculdade de Medicina, Instituto de Farmacologia e Terapeutica Experimental, IBILI, Universidade de Coimbra, Coimbra, Portugal

**Instituto de Ciencias Biomedicas Abel Salazar, Universidade do Porto, Porto, Portugal

��Centro de Investigacao em Ciencias Saude, Universidade da Beira Interior, Covilha, Portugal

CorrespondenceSusana Coimbra.

E-mail: [email protected]

Accepted for publication9 August 2010

Key wordscytokines, growth factors, narrowband ultraviolet

B, psoralen–ultraviolet A, psoriasis therapy,

psoriasis vulgaris

Conflicts of interestNone declared.

DOI 10.1111/j.1365-2133.2010.09992.x

Summary

Background Several cross-sectional studies have shown that different cytokines andgrowth factors are enhanced in psoriasis.Objectives We aimed to understand the role ⁄relation of interleukin (IL)-22, IL-17,IL-23, IL-8, vascular endothelial growth factor (VEGF) and tumour necrosis fac-tor (TNF)-a in psoriasis vulgaris, addressing their levels and changes before,during and after psoralen–ultraviolet A (PUVA) and narrowband ultraviolet B(NB-UVB) treatment.Methods A cross-sectional and a longitudinal study (n = 34) – before (T0) and at3 (T3), 6 (T6) and 12 (T12) weeks of NB-UVB and PUVA therapy – were per-formed; 17 patients started NB-UVB and 17 PUVA, and IL-22, IL-17, IL-23, IL-8,TNF-a and VEGF levels were evaluated.Results At T0, compared with controls (n = 20), all the parameters were signifi-cantly higher in patients, except for TNF-a. Both NB-UVB and PUVA treatmentgave, at T3, a significant decrease in TNF-a and IL-23; IL-22 and IL-17 decreasedsignificantly at T6; all parameters and Psoriasis Area and Severity Index decreasedsignificantly at T12. However, in both groups, at T12, VEGF was still signifi-cantly higher than control.Conclusions Psoriasis seems to be a complex disease in which the cytokine networkis disturbed, namely in levels of IL-22, IL-17, IL-23, IL-8, TNF-a and VEGF.NB-UVB and PUVA follow-up studies suggested that the reduction in theIL-23 ⁄Th17 axis might be important in the pathogenic mechanisms of psoriasis.Further follow-up studies of patients with psoriasis treated with these and othertherapies could be very helpful for the understanding of the disturbance in thecytokine network in psoriasis and indirectly in its pathogenesis.

Psoriasis vulgaris is a chronic relapsing hyperproliferative skin

disease, characterized histologically by acanthosis, parakeratosis

and dermal infiltration of mononuclear cells such as T cells,

dendritic cells (DCs) and monocytes ⁄macrophages; neutrophilic

infiltrates and the development of elongated ⁄hyperplastic

blood vessels in the papillary dermal region can also be

observed.1–3 All these cells, given their ability to link the

innate and acquired immune systems and to regulate cytokine

� 2010 The Authors

1282 BJD � 2010 British Association of Dermatologists 2010 163, pp1282–1290

production, seem to contribute to establish the psoriatic le-

sions.

Psoriasis is currently accepted as a T-helper (Th) 1 ⁄Th17

inflammatory disease, and it is therefore associated with an

increase of Th1 and Th17 cytokines.2,3 Interleukin (IL)-23,

produced by DCs and by macrophages, has the potential to

activate T cells, stimulating survival and proliferation of Th17

cells.4 It seems also to induce dermal infiltration by mixed

inflammatory cells and acanthosis.5 As IL-23 stimulates

tumour necrosis factor (TNF)-a and IL-22 expression, its

deregulation has been proposed as a causative factor in psoria-

sis onset.6

Th17 cells are characterized by the production of IL-22 and

IL-17.7 IL-22 induces epidermal hyperplasia and hypogranulo-

sis; it also induces proinflammatory responses such as the

production of cytokines, chemokines and acute-phase proteins

from many cell types, and it regulates the differentiation and

migration of keratinocytes. The production of IL-22 is directly

induced by IL-23, and IL-22 can mediate IL-23-induced acan-

thosis and dermal inflammation.8,9 The production of IL-22 is

upregulated in psoriatic skin,7 and high blood levels of IL-22

are correlated with psoriasis severity.10 IL-17 is a critical com-

ponent in the establishment and perpetuation of inflammation,

inducing the production of proinflammatory cytokines, mainly

by endothelial cells and macrophages.11 It also activates kerati-

nocytes to produce ILs such as IL-8.12 Increased levels of IL-17

have been found in skin lesions and in blood of patients with

psoriasis, and they were correlated with psoriasis severity.13–16

TNF-a is involved in the regulation of keratinocyte prolifer-

ation. It also influences the activation, proliferation and differ-

entiation of many other cells, and enhances the synthesis of

several cytokines.12 TNF-a seems to increase the expression of

IL-8.1,2 Dermal macrophages in the papillary dermis could be

the main source of TNF-a in psoriatic skin, although it might

also be produced by DCs, T cells and keratinocytes.3,17,18

IL-8, produced by keratinocytes,19 induces neutrophil

mobilization and degranulation.12,20 A significant rise in IL-8

levels has been observed in psoriasis.15,21,22

The vascular endothelial growth factor (VEGF) released

from keratinocytes appears to contribute to the vascularization

of the lesions in psoriasis.23 It can stimulate epidermal hyper-

plasia, vascular growth, and leucocyte infiltration in the

skin,24 and can induce proliferation, sprouting, migration and

tube formation of endothelial cells. Moreover, it increases the

permeability of the endothelium and causes vasodilatation.25

In psoriasis, VEGF levels are significantly higher in skin

lesions, its plasma concentrations are raised during the active

stage,26–29 and both skin and plasma levels have been posi-

tively correlated with Psoriasis Area and Severity Index

(PASI).23,29 As angiogenesis is particularly dependent on

VEGF,30 its role in psoriasis seems to be a key factor in the

link between inflammation and angiogenesis.31 All data about

VEGF in psoriasis suggest that it might be a central growth

factor in psoriasis pathology, and that the manipulation of

VEGF levels could be another promising therapeutic approach

for inflammatory diseases such as psoriasis.

Several cross-sectional studies have shown that different

cytokines and growth factors are enhanced in psoriasis. How-

ever, few longitudinal studies have been performed, address-

ing the levels and changes in those cytokines and growth

factors before, during and after treatment. These studies could

contribute to a better understanding of psoriasis pathogenesis

and on the efficacy of the therapies used.

Psoriatic lesions seem to be the result of the interaction of

several different cell types, and there seems to be a close inter-

dependence between these cells and their activation products.

The aim of the present work was to understand the role and the

cross-talk between some inflammatory cytokines and growth

factors (IL-22, IL-17, IL-23, IL-8, TNF-a and VEGF) that are

produced or that induce the different cell types (macrophages,

DCs, lymphocytes, neutrophils, keratinocytes) present in the

psoriatic lesions. With that perspective, we evaluated their

blood levels during psoralen–ultraviolet (UV) A (PUVA) and

narrowband UVB (NB-UVB) treatment ⁄ improvement. We per-

formed a cross-sectional and a longitudinal study – before, and

3, 6 and 12 weeks after commencing therapy – in Portuguese

patients with psoriasis vulgaris.

Materials and methods

Subjects

The protocol used was approved by the Committee on Ethics

of the University Hospital of Coimbra; all the 34 patients pre-

sented chronic psoriasis vulgaris and gave informed consent to

participate in the study. Psoriasis severity was evaluated by

PASI.32 To diminish subjectivity, PASI was evaluated by the

same dermatologist. Psoriasis was diagnosed between 2

months and 55 years before the present study. All patients

were studied clinically and analytically in an active phase of

the disease (T0), meaning exacerbation of psoriatic lesions,

and 3 (T3), 6 (T6) and 12 (T12) weeks after commencing

treatment. Of the 34 patients, 17 received PUVA therapy and

17 were treated with NB-UVB radiation. The type of treatment

was decided by the patient’s dermatologist, according to sever-

ity of the disease presentation and to the clinical and therapeu-

tic history. Afterwards, patients were invited to participate in

the study. Patients in the NB-UVB and PUVA groups presented

similar characteristics regarding age (mean ± SD 41 ± 16 vs. 48

± 15 years, respectively; P = 0Æ131), duration of the disease

(mean ± SD 16 ± 11 vs. 23 ± 13 years, respectively; P =

0Æ099), gender (11 women ⁄six men and nine women ⁄eight men, respectively), body mass index [median (interquar-

tile range, IQR) 28Æ6 (21Æ9–29Æ9) vs. 27Æ7 (26Æ1–29Æ6),

respectively; P = 0Æ540] and PASI [median (IQR) 17Æ2 (12Æ6–

25Æ0) vs. 26Æ5 (13Æ7–34Æ8), respectively; P = 0Æ057].

NB-UVB irradiation (311 ± 2 nm) was administered using

a Waldmann 7001K cabinet (UVA ⁄UVB–TL-01; Waldmann

Medizintechnik, Villigen-Schwenningen, Germany); the initial

dose, dependent on the phototype of the patient, was 0Æ1–0Æ3J cm)2, and an increasing dose schedule based on an increase

of 0Æ1 J cm)2 was used at each session (thrice weekly), until a


BJD � 2010 British Association of Dermatologists 2010 163, pp1282–1290

Psoriasis vulgaris cytokines and PUVA ⁄NB-UVB therapy, S. Coimbra et al. 1283

maximum dose of 2Æ5 J cm)2 was reached. UVA irradiation

(320–400 nm) was administered using the same cabinet, and

8-methoxypsoralen (0Æ6 mg kg)1) was administered 2 h

before. The initial dose was 2–3 J cm)2, according to the

phototype; an increasing dose schedule based on an increase

of 0Æ5 J cm)2 was used at each session (thrice weekly), until a

maximum dose of 12 J cm)2 was reached. Eyes and genitals

were shielded during the irradiation procedures.

The control group included 20 healthy volunteers without

psoriasis or other skin disease and with normal haematological

and biochemical values. Patients and controls were cross-

matched for age (mean ± SD 45 ± 16 vs. 44 ± 14 years,

respectively; P = 0Æ821), gender (20 women ⁄14 men and 11

women ⁄nine men, respectively) and body mass index [med-

ian (IQR) 28Æ1 (23Æ6–29Æ7) vs. 25Æ6 (23Æ5–29Æ6), respectively;

P = 0Æ329].

Patients and controls presenting other skin diseases, diabetes

mellitus, inflammatory or infectious diseases, or cardiovascular,

liver or kidney diseases were excluded from the study. None of

the patients received any treatment for at least 1 month prior

to inclusion.

Collection and preparation of blood samples

Blood from nonfasted subjects was collected in order to obtain

plasma (anticoagulant used: heparin lithium) and serum. None

of the collected samples was icteric or haemolysed.

Assays

The IL-22, IL-23, IL-8, TNF-a and VEGF plasma levels and the

IL-17 serum levels were evaluated by enzyme immunoassays:

Human IL-22 Immunoassay (R&D Systems, Minneapolis, MN,

U.S.A.), Human IL-23 enzyme-linked immunosorbent assay

(ELISA), Human IL-8 ⁄NAP-1 ELISA, Human TNF-a ELISA and

Human VEGF-A ELISA (Bender MedSystems, Vienna, Austria)

and Human IL-17 Immunoassay (R&D Systems), respectively.

Statistical analysis

The statistical analysis was performed using the Statistical

Package for Social Sciences version 16 for Windows (SPSS,

Chicago, IL, U.S.A.). To evaluate the differences between

groups we used the Mann–Whitney test. To evaluate the dif-

ferences between active stage of disease and the end of treat-

ment, we used the Wilcoxon test. Measurements are expressed

as median (IQR). P < 0Æ05 was considered as statistically

significant. The correlation analysis was performed by calculat-

ing the Spearman correlation coefficient.

Results

Before starting a therapy, in the active stage of the disease,

our studied patients presented moderate to severe forms of

psoriasis vulgaris as shown by a median (IQR) PASI33 of 22Æ6(12Æ7–29Æ9).

Patients with psoriasis presented several significant disturb-

ances, as compared with controls, namely higher levels of

IL-22, IL-17, IL-23, IL-8 and VEGF, and a trend towards

higher TNF-a values (Table 1). We also observed, in the

active stage of the disease, a significant positive correlation

between PASI and TNF-a (r = 0Æ441; P = 0Æ009), between

PASI and IL-8 (r = 0Æ345; P = 0Æ046) and between TNF-a and

VEGF (r = 0Æ418; P = 0Æ014).

When comparing the NB-UVB and PUVA groups, before

starting the treatment, we found that patients who underwent

PUVA therapy showed significantly higher values of IL-8 (P =

0Æ041). At T3, IL-8 levels were still significantly higher in

patients treated with PUVA (P = 0Æ031); at T6, PUVA patients

presented significantly higher levels of IL-22 (P = 0Æ045). No

other differences were observed.

Concerning patients treated with NB-UVB (Fig. 1), we

observed that before starting the therapy they presented signif-

icantly higher levels of VEGF, IL-22, IL-17 and IL-23, as well

as a trend towards higher values of IL-8 and TNF-a, when

compared with controls. At T3, a significant decrease was

already observed for TNF-a and IL-23. IL-22 and IL-17 pre-

sented a significant decrease at T6 and TNF-a and IL-23 sus-

tained their lower values. At T12, alongside a significant

improvement in PASI, we found a statistically significant

decrease for all parameters studied: IL-22, IL-17, IL-23, IL-8,

TNF-a and VEGF. All decreased to normal values (similar to

control values), except VEGF which still presented a signifi-

cantly higher value.

Patients treated with PUVA (Fig. 2), in the active stage of

the disease, before starting the treatment, presented signifi-

cantly higher levels of all the cytokines and growth factors

studied, when compared with controls. TNF-a and IL-23, as

with NB-UVB treatment, presented a significant reduction at

T3. After 6 weeks of therapy, IL-23, IL-22 and IL-17 pre-

sented significantly lower values. At T12, alongside a signifi-

cant reduction in PASI, we found a significant decrease in all

the parameters studied. Although a significant decrease was

observed for VEGF at the end of the treatment, as in the

NB-UVB group the plasma levels were still significantly higher

than those presented by the control group.

Table 1 Plasma levels of interleukin (IL)-22, IL-17, IL-23, IL-8,tumour necrosis factor (TNF)-a and vascular endothelial growth factor

(VEGF) in controls and in patients with psoriasis

Controls

(n = 20)

Patients

(n = 34) P-value

IL-22 (pg mL)1) 17Æ5 (2Æ7–41Æ0) 48Æ5 (20Æ1–69Æ6) 0Æ001IL-17 (pg mL)1) 0Æ9 (0Æ7–2Æ2) 6Æ9 (5Æ3–8Æ8) < 0Æ001

IL-23 (pg mL)1) 50Æ1 (34Æ2–66Æ5) 70Æ5 (62Æ6–82Æ7) < 0Æ001IL-8 (pg mL)1) 11Æ8 (4Æ4–17Æ9) 20Æ4 (9Æ6–30Æ2) 0Æ031

TNF-a (pg mL)1) 1Æ0 (0Æ5–1Æ6) 1Æ3 (0Æ6–2Æ5) 0Æ151VEGF (pg mL)1) 54Æ2 (5Æ1–80Æ8) 145Æ2 (46Æ8–251Æ4) 0Æ001

Values are expressed as median (interquartile range).



1284 Psoriasis vulgaris cytokines and PUVA ⁄NB-UVB therapy, S. Coimbra et al.

Concerning the changes in the parameters studied with

NB-UVB and PUVA therapies (Fig. 3), we found that all para-

meters improved and that the improvement was higher for

the treatment with PUVA, reaching statistical significance in

PASI and in IL-23 level, as compared with patients treated

with NB-UVB.

(a)

(b)

(e) (f) (g)

(c) (d)

30·0

******

***

***

** **

***

* ****

**

*

**

***

*

******

***

25·0

20·0

15·0

10·0

5·0

0·0

12·0 120·0

100·0

80·0

60·0

40·0

20·0

0·0

500·0

400·0

300·0

200·0

100·0

0·0

10·0

8·0

6·0

4·0

2·0

0·0

4·0

3·0

2·0

1·0

0·0

100·0

80·0

60·0

40·0

20·0

0·0

70·0

65·0

60·0

55·0

50·0

45·0

40·0

35·0

30·0

25·0

20·0

15·0

10·0

5·0

0·0

T0 T3 T6 T12 T0 T3 T6 T12 T0 T3 T6 T12

T0 T3 T6 T12T0 T3 T6 T12

T0

PAS

I

IL-1

7 (p

g m

L–1

)

IL-2

2 (p

g m

L–1

)

IL-2

3 (p

g m

L–1

)

TN

F-α

(p

g m

L–1

)

IL-8

(p

g m

L–1

)

VE

GF

(p

g m

L–1

)

ControlControl

Control Control

Control

Control

T3 T6 T12

T0 T3 T6 T12

Fig 1. Box and whisker plots showing values of Psoriasis Area and Severity Index (PASI) (a), interleukin (IL)-22 (b), IL-17 (c), IL-23 (d), IL-8

(e), tumour necrosis factor (TNF)-a (f) and vascular endothelial growth factor (VEGF) (g) in controls and in patients with psoriasis treated with

narrowband ultraviolet B. All patients were studied in an active phase of the disease, before commencing treatment (T0), and at 3 (T3), 6 (T6)

and 12 (T12) weeks of treatment. *P < 0Æ05; **P £ 0Æ01; ***P £ 0Æ001.




Concerning 75% improvement in PASI (PASI 75) response,

we found that 24 patients achieved a positive response but 10

did not (eight in the NB-UVB and two in the PUVA group).

As there is strong evidence demonstrating that 50% improve-

ment in PASI (PASI 50) could also be a clinically meaningful

endpoint,34 we calculated the PASI 50 response, and observed

T0 T3 T6 T12Control T0 T3 T6 T12Control T0 T3 T6 T12Control

T0 T3 T6 T12Control

0·0

50·0

45·0

40·0

35·0

30·0

25·0

20·0

15·0

10·0

5·0

0·0

50·0(a)

(b) (c) (d)

(e) (f) (g)

******

***

***

***

***

*** *

***

***

******

*

*** **

*** ******

****

45·0

40·0

35·0

30·0

25·0

PAS

I

IL-2

2 (p

g m

L–1

)

IL-1

7 (p

g m

L–1

)

IL-2

3 (p

g m

L–1

)

IL-8

(p

g m

L–1

)

TN

F-α

(p

g m

L–1

)

VE

GF

(p

g m

L–1

)

20·0

15·0

10·0

5·0

0·0

20·02·0

4·0

6·0

8·0

10·0

12·0

0·0

2·0

4·0

6·0

8·0

10·0

0·0 0·0

100·0

200·0

300·0

400·0

500·0

600·0

3·0

5·0

7·0

9·0

1·0

40·0

60·0

80·0

100·0

0·0

20·0

40·0

60·0

80·0

100·0

T0 T3 T6 T12

T0 T3 T6 T12Control T0 T3 T6 T12Control

Fig 2. Box and whisker plots showing values of Psoriasis Area and Severity Index (PASI) (a), interleukin (IL)-22 (b), IL-17 (c), IL-23 (d), IL-8

(e), tumour necrosis factor (TNF)-a (f) and vascular endothelial growth factor (VEGF) (g) in controls and in patients with psoriasis treated with

psoralen–ultraviolet A. All patients were studied in an active phase of the disease, before commencing treatment (T0), and at 3 (T3), 6 (T6) and

12 (T12) weeks of treatment. *P < 0Æ05; **P £ 0Æ01; ***P £ 0Æ001.




that only three patients (all under NB-UVB therapy) did not

achieved a positive response. However, the only statistically

significant differences between responders and nonresponders

observed for PASI 50 were the IL-17 levels at T0 (P = 0Æ034)

and the PASI at T12 (P = 0Æ002); for PASI 75 only the PASI at

T12 (P < 0Æ001) was significantly different.

Discussion

Nowadays, it is accepted that all the different cells involved in

the psoriatic lesions, such as T cells, DCs, macrophages, endo-

thelial cells, neutrophils and keratinocytes, have at different

stages of the disease an important role in its pathogenesis. None

the less, the chronology of the events that lead to the establish-

ment of the lesions is not completely understood. Even so, it is

accepted that the products of activation of these cells, namely

acute-phase reactants, cytokines and growth factors, play an

important role.1,2,35–37 However, the cross-talk between cyto-

kines and growth factors during the different therapeutic

approaches used to treat psoriasis is poorly clarified. Most

reports address only one or a few cytokines and growth factors

and do not evaluate their changes during treatment.

In the present study, we evaluated different cytokines and

growth factors that might reflect the activity of the cells usu-

ally present in the psoriatic lesions, in the active stage of the

disease, during and after the treatment. We considered that

this evaluation, from the active stage of psoriasis to clearing of

the lesions, could provide information about the cross-talk

between those cytokines and growth factors.

We found that before commencing therapy, patients with

psoriasis vulgaris presented significantly higher IL-22, IL-17,

IL-23, IL-8 and VEGF plasma levels, when compared with con-

trols. These results are consistent with others10,13–16,21–23,26–28

reported in the literature, suggesting that all play an important

role in the pathogenesis of psoriasis. TNF-a presented only a

trend towards higher values; however, it showed a positive

significant correlation with the severity of the disease, as

defined by PASI, in accordance with other studies.18,38 Studies

on plasma TNF-a levels in psoriasis are not consist-

ent.15,21,22,39,40 Some authors suggested that this cytokine is

produced and acts mainly locally,12 and therefore plasma levels

might be lower than at the inflammatory area. Moreover,

VEGF, a central regulator of angiogenesis, correlated positively

and significantly with TNF-a, supporting the hypothesis that

in psoriasis, inflammation is strongly linked to angiogenesis

and reflects the extent of psoriatic skin involvement.

As far as we know, there are no studies performing the

simultaneous evaluation of the blood levels of TNF-a, IL-8,

IL-22, IL-17, IL-23 and VEGF in patients with psoriasis vulga-

ris, before and during a period of 12 weeks of therapy with

NB-UVB and PUVA. We found that both NB-UVB and PUVA

treatment produced significant reductions in IL-22, IL-17,

IL-23, IL-8, TNF-a and VEGF, reflecting the observed improve-

ment of the lesions and the reduction in proinflammatory

signals. The literature is controversial16,41–45 about the effect of

psoriasis therapies on the cytokines and growth factors that we

studied, probably because different periods of evaluation were

used. Indeed, only blood levels of cytokines and growth factors

measured during the same time of treatment and using the

same dose of irradiation should be compared.

During treatment with both NB-UVB and PUVA, a decrease

in IL-23 and TNF-a was observed at T3, followed by a

decrease in IL-22 and IL-17 at T6, and finally, a decrease in

VEGF and IL-8 at T12. These results suggest that both thera-

pies have a strong action upon DCs and macrophages, as

shown by the significant decrease in IL-23 and TNF-a at T3;

the reduction in IL-23 may explain the subsequent interfer-

ence with T cells, namely with Th17 cells, as suggested by the

observed reduction in IL-22 and IL-17 at T6; the reduction in

these cytokines, IL-22 and IL-17, seems to contribute to nor-

malize keratinocytes, explaining the subsequent decreases

observed in VEGF and IL-8 at T12. In considering these

changes, linked to clearing of the lesions, we propose an

immuno-inflammatory pathway for psoriasis that involves the

PASI

0·00

–5·00

–10·00

–15·00 **

**

*

*

–20·00

–25·00

–30·00

0·00

–5·00

–10·00

–15·00

–20·00

–25·00

–30·00

IL-22 IL-17 IL-23

NBUVBIL-8 TNF-α VEGF PASI IL-22 IL-17 IL-23

PUVAIL-8 TNF-α VEGF

Fig 3. Median values of the changes observed

following treatment of psoriasis vulgaris with

narrowband ultraviolet B (NB-UVB) and

psoralen–ultraviolet A (PUVA), for Psoriasis

Area and Severity Index (PASI), interleukin

(IL)-22, IL-17, IL-23, IL-8, tumour necrosis

factor (TNF)-a and vascular endothelial

growth factor (VEGF). *P (NB-UVB vs. PUVA)

< 0Æ05; **P (NB-UVB vs. PUVA) £ 0Æ01.




production of IL-23, as well as TNF-a, from DCs, which cause

activation and proliferation of Th17 cells. Subsequently, Th17

cells induce the expression of IL-22 and IL-17. IL-22 induces

keratinocyte hyperplasia and mediates IL-23-induced dermal

inflammation and acanthosis. On the other hand, IL-17

induces keratinocyte activation to produce several ILs such as

IL-8. Indeed, IL-8 secretion appears to be stimulated not only

by TNF-a but also by IL-17.12 IL-8 induces neutrophil mobili-

zation and activation, characteristic of active psoriatic

lesions.46,47 Activation of keratinocytes also leads to an

increase in their own proliferation with altered maturation

and to the production of several inflammatory mediators that

might cause further recruitment of immune cells and activa-

tion of stromal cells. Furthermore, as a result of keratinocyte

activation, VEGF is produced, contributing to induction of

angiogenesis, characteristic of psoriasis lesions. Therefore, the

involvement of the IL-23 ⁄Th17 axis in psoriasis seems to be a

key event in its pathogenesis, explaining some of the typical

histological characteristics of the psoriatic lesions, such as

hyperplasia of keratinocytes (by IL-22) and the neutrophil

infiltration (IL-8 production induced by IL-17). The release of

activation products occurs as a consequence of neutrophil acti-

vation, as we reported previously.48 TNF-a is known to

induce the production of IL-6, and both cytokines are able to

trigger the synthesis and release of C-reactive protein (CRP);49

indeed, the rise in blood levels of CRP and a correlation

between CRP and the severity of psoriasis vulgaris, as defined

by PASI, was reported recently in patients with psoriasis,48

confirming psoriasis as a condition in which systemic inflam-

matory response is marked.

The rapid decrease in IL-23 after starting NB-UVB and PUVA

therapies seems to reverse several of the sequential changes

reported (Fig. 4). It has been proposed6 that IL-23 deregula-

tion might be an independent causative factor in the pathogen-

esis of psoriasis, as it sets in motion several pathways leading

to neutrophil recruitment, and stimulates the production of

other cytokines, which may directly act on keratinocytes in a

TNF-regulated way, resulting in epidermal hyperplasia and ⁄or

altered keratinocyte differentiation. Furthermore, the IL-23 ⁄Th17 axis is believed to be crucial in psoriasis pathogenesis,50

and its inhibition appears to be central to therapeutic success.

This is supported by the association of IL23R gene variants

with psoriasis risk,51,52 and by the therapeutic success of the

monoclonal antibody that binds to the p40 subunit of IL-23

NBUVB or PUVA

Kc Kc

3rd week 6th week 12th week

KcDC

McKc

Keratinocytehyperplasia

VEGF

Development ofelongated/hyperplasticblood vessels

Neutrophilmobilization and

degranulation

Kc Kc

KcKc

Kc KcKc

Kc Kc

IL-23

TNF-α

Th17

Th1

IL-17

IL-22

IL-8

T cells

Kc

Fig 4. The effect of narrowband ultraviolet B (NB-UVB) and psoralen–ultraviolet A (PUVA) therapies on interleukin (IL)-22, IL-17, IL-23, IL-8,

tumour necrosis factor (TNF)-a and vascular endothelial growth factor (VEGF), and their potential role in psoriasis. DC, dendritic cell; Kc,

keratinocyte; Mc, macrophage; Th, T-helper.




and IL-12.53 Our results support this hypothesis, as the reduc-

tion in IL-23 (the first change observed with treatment of the

disease) seems to be crucial for the subsequent changes

observed for the other cytokines. Our data are consistent with

the concept54 that the response to psoriasis therapy is depen-

dent on the inactivation of DC products, and inactivation of,

besides the Th1, the Th17 immune response.

Despite the similar final changes observed for both thera-

pies, the improvements were higher in patients treated with

PUVA, which may explain its higher remission rate, as com-

pared with NB-UVB.55

After both types of therapies, all cytokines returned to values

similar to those presented by the control; only VEGF was still

significantly higher than the control. NB-UVB irradiation is

known to upregulate VEGF;56 however, similar results were

found for patients treated with PUVA. Sustained high levels of

VEGF, even at remission, as defined by PASI, suggest that VEGF

might be important in defining the time of remission, as VEGF

is known to promote vascular permeability that enhances leuco-

cyte traffic into the skin and alters the dermal capillaries to

express leucocyte chemoattractant molecules.57 Moreover, we

found48 that a residual inflammation persists after treatment with

PUVA and NB-UVB, as CRP was still higher than the control.

We wonder if this residual inflammatory stimulus, along with

higher VEGF levels, could favour infiltration of inflammatory

cells into the skin and, therefore, the development of lesions.

In summary, psoriasis seems to be a complex disease in

which the cytokine network is disturbed, namely in blood

levels of IL-22, IL-17, IL-23, IL-8, TNF-a and VEGF. Our fol-

low-up studies of patients with psoriasis treated with NB-UVB

and PUVA suggest that the reduction in the IL-23 ⁄Th17 axis

might be important in the pathogenic mechanisms of psoria-

sis. Further follow-up studies of patients with psoriasis treated

with these and other therapies could be very helpful for the

understanding of the disturbance in the cytokine network in

psoriasis and indirectly in its pathogenesis.

What’s already known about this topic?

• Cross-sectional studies have shown that different cyto-

kines and growth factors are enhanced in psoriasis.

What does this study add?

• This is a cross-sectional ⁄ longitudinal study that aims to

elucidate the role ⁄relation of some inflammatory cyto-

kines and growth factors [interleukin (IL)-22, IL-17,

IL-23, IL-8, tumour necrosis factor-a and vascular endo-

thelial growth factor] in psoriasis vulgaris before, during

and after psoralen–ultraviolet A and narrowband ultra-

violet B treatment of Portuguese patients. This study is

intended to contribute to a better understanding of pso-

riasis pathogenesis and the efficacy of therapies used.

Acknowledgments

This study was supported by Fundacao para a Ciencia e Tecno-

logia (FCT: POCI ⁄SAU – OBS ⁄58600 ⁄2004) and Fundo Euro-

peu de Desenvolvimento Regional (FEDER).

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