Invest Clin 66(4): 426- 435, 2025 https://doi.org/10.54817/IC.v66n4a06

Corresponding author: Zizhou Zhang. Department of Respiratory and Critical Care Medicine, Changzhou Seventh

People’s Hospital (Changzhou Geriatric Hospital Affiliated with Soochow University), Changzhou 213011, Jiangsu

Province, China. Email: zhangzzcsph@ph-edu.cn

Correlations of interleukin-17 and regulatory

T cells with the severity of chronic obstructive

pulmonary disease and pulmonary function.

Jun Chen, Tingting Zhao, Yingying Gao and Zizhou Zhang

Department of Respiratory and Critical Care Medicine, Changzhou Seventh People’s

Hospital (Changzhou Geriatric Hospital Affiliated With Soochow University),

Changzhou, Jiangsu Province, China.

Keywords: Pulmonary Disease, Chronic Obstructive; Correlation Measures; Interleukins;

Respiratory Function Tests; T-Lymphocytes, Regulatory; Disease Severity.

Abstract. We aimed to explore the correlation of interleukin-17 (IL-17)

and regulatory T (Treg) cells with the severity of chronic obstructive pulmo-

nary disease (COPD) and pulmonary function. A total of 90 COPD patients,

all with a confirmed diagnosis of COPD and without any history of asthma,

were included to ensure that the findings are specific to COPD. In addition,

a smoking group (healthy smokers, n=90) and a healthy group (healthy non-

smokers, n=90) were studied. The COPD group had the highest IL-17 level and

the lowest cluster of differentiation 4 (CD4) + Treg cell count, CD25+Treg

cell count, and CD4+CD25+Treg cell count in peripheral blood, followed by

the smoking and healthy groups (p<0.05). The CD4+ Treg cell count, CD25+

Treg cell count, CD4+CD25+ Treg cell count, forced vital capacity (FVC), forced

expiratory volume in one second (FEV1), and FEV1/FVC were found to be the

highest in the mild group, followed by those of moderate and severe groups

(p<0.05). The CD4+ Treg cell count, CD25+ Treg cell count, and CD4+CD25+

Treg cell count displayed positive correlations with FEV1, FVC, and FEV1/FVC

(r>0, p<0.05) and negative correlations with the IL-17 level (r<0, p<0.05).

The IL-17 level was negatively correlated with FEV1, FVC, and FEV1/FVC (r<0,

p<0.05). Importantly, this study highlights the combined analysis of IL-17 and

Treg subsets, which provides additional insights into their joint association with

COPD severity beyond IL-17 alone.

Correlations of interleukin-17 and regulatory T cells with COPD 427

Vol. 66(4): 426 - 435, 2025

Correlación de la interleucina-17 y las células T reguladoras

con la gravedad de la enfermedad pulmonar obstructiva crónica

y la función pulmonar.

Invest Clin 2025; 66 (4): 426 – 435

Palabras clave: Enfermedad Pulmonar Obstructiva Crónica; Medidas de Correlación;

Interleucinas; Pruebas de Función Respiratoria; Linfocitos T

Reguladores; Gravedad de la Enfermedad.

Resumen. Nuestro objetivo fue explorar las correlaciones entre la interleu-

cina-17 (IL-17) y las células T reguladoras (Treg), así como entre la gravedad

de la enfermedad pulmonar obstructiva crónica (EPOC) y la función pulmonar.

Se compararon los datos de un grupo con EPOC (pacientes con EPOC trata-

dos entre junio de 2020 y septiembre de 2023, n=90), un grupo de fumadores

(fumadores sanos, n=90) y un grupo control (no fumadores sanos, n=90). El

grupo de EPOC presentó el nivel más alto de IL-17 y el recuento más bajo de

células Treg CD4+, CD25+ y CD4+CD25+ en la sangre periférica, seguido

por los grupos de fumadores y de control (p<0,05). El recuento de células

Treg CD4+, células Treg CD25+, células Treg CD4+CD25+, la capacidad vital

forzada (FVC), el volumen espiratorio forzado en el primer segundo (FEV1) y la

relación FEV1/FVC fueron más altos en el grupo leve de EPOC, seguido por los

grupos moderado y severo (p<0,05). El recuento de células Treg CD4+, célu-

las Treg CD25+ y células Treg CD4+CD25+ mostró correlaciones positivas con

FEV1, FVC y FEV1/FVC (r>0, p<0,05) y correlaciones negativas con el nivel

de IL-17 (r<0, p<0,05). El nivel de IL-17 se correlacionó negativamente con

FEV1, FVC y FEV1/FVC (r<0, p<0,05). La detección combinada de IL-17 y de

subconjuntos de Treg es útil para aumentar el valor predictivo de estos en la

aparición de EPOC.

Received: 02-03-2025 Accepted: 04-11-2025

INTRODUCTION

Chronic obstructive pulmonary disease

(COPD), a chronic inflammatory disease, is

pathologically characterized by airflow ob-

struction of the respiratory tract, and COPD

patients usually develop fatigue, shortness of

breath, cough, and other typical respiratory

symptoms 1,2. In China, the incidence rate of

COPD is 13.6% in people aged over 40 years

old and as high as 24.8% in the elderly 3. The

specific pathogenesis of COPD has not been

fully elucidated. Still, it is mainly believed to

involve mechanisms such as oxidative/anti-

oxidative imbalance, chronic inflammatory

responses in the airways and pulmonary pa-

renchyma, and protein/anti-protein imbal-

ance 4. A study reported that T lymphocytes

act as vital players in modulating airway

inflammation in COPD, in which helper T

(Th) cells are the major players 5. Cluster of

differentiation 4 (CD4)+ T lymphocytes be-

long to Th lymphocytes, and activated CD4+

T lymphocytes can be classified into Th17

cells and regulatory T (Treg) cells. Th17 and

Treg cells repress and antagonize each oth-

428 Chen et al.

Investigación Clínica 66(4): 2025

er during differentiation, and their balance

can confer immune tolerance, whereas an

imbalance can induce various autoimmune

and infectious diseases 6. Th17 triggers and

progressively amplifies immune responses

primarily through the generation of inter-

leukin-17 (IL-17), and a sustained increase

in IL-17 content will induce neutrophilic

chronic inflammation. As a result, airway in-

flammation and progressive airway obstruc-

tion emerge 7.

Based on this, in the present study, the

levels of IL-17 and Treg subsets in the pe-

ripheral blood of COPD patients were mea-

sured, and their correlations with COPD

occurrence and pulmonary function were in-

vestigated, aiming to identify targets for the

prevention and treatment of COPD.

MATERIALS AND METHODS

Subjects

COPD patients visiting our hospital

from June 2020 to September 2023 (a COPD

group, n=90), healthy smokers (a smoking

group, n=90), and healthy non-smokers (a

healthy group, n=90) were enrolled as sub-

jects. The COPD group was composed of 53

males and 37 females aged 49-83 years old,

with an average age of (58.52 ± 4.87) years

old. The body mass index (BMI) was (22.08

± 1.87) kg/m2, the number of cigarettes

smoked was (400.36 ± 78.98) cigarettes/

year, and the course of disease was (5.64 ±

1.75) years. As to the severity [according to

the 2019 Global Initiative for Chronic Ob-

structive Lung Disease (GOLD) criteria] 8,

there were 30 mild cases, 42 moderate cas-

es, and 28 severe cases. The smoking group

consisted of 51 males and 39 females aged

45-81 years old, with a mean of (59.48 ±

5.26) years old. BMI was (21.98 ± 1.58) kg/

m2, and the number of cigarettes smoked

was (409.54 ± 82.59) cigarettes/year. In the

healthy group composed of 55 males and 35

females, the age was 45-80 years old, with an

average of (59.11 ± 5.59) years old, and MI

was (22.19 ± 1.67) kg/m2. The age, gender,

and BMI were comparable among the three

groups (p>0.05).

Inclusion and exclusion criteria

The following inclusion criteria were

employed: 1) COPD patients meeting the

diagnostic criteria for COPD and without a

history of acute exacerbation in the past six

months 8, 2) smokers with expected results

in the pulmonary function test and number

of cigarettes smoked ≥200 cigarettes/year,

and non-smokers with expected results in

the pulmonary function test and no smok-

ing history, and 3) subjects who voluntarily

signed the informed consent form.

The exclusion criteria involved: 1) sub-

jects requiring mechanical ventilation due

to severe condition, 2) those with rheumatic

system diseases, allergic diseases or immune

deficiencies, 3) those with acute pulmonary

embolism, tuberculosis, bronchiectasis,

asthma, cystic fibrosis, and other respira-

tory diseases, 4) those with coagulation dys-

function, 5) those with severe dysfunction of

multiple organs, 6) those with a previous his-

tory of pulmonary surgery or lung tumors,

7) those with severe arrhythmia, acute myo-

cardial infarction or myocardial ischemia,

or 8) those taking immunosuppressants or

glucocorticoids within 4 weeks before enroll-

ment.

Detection of indicators in the peripheral

blood

Peripheral venous blood (6 mL, evenly

split into two portions) was collected before

treatment in the COPD group and on the day

of physical examination in the smoking and

healthy groups. One portion was subjected to

heparin anticoagulation, followed by 10 min

of centrifugation (centrifugation radius: 6.5

cm, and centrifugation rate: 3500 rpm). Next,

the supernatant was harvested for an enzyme-

linked immunosorbent assay (Cat. No. DLR-

IL17-Hu, Wuxi Donglin Sci & Tech Develop-

ment Co., Ltd., China) to measure IL-17

levels. The other portion was subjected to Fi-

coll density gradient centrifugation using the

Correlations of interleukin-17 and regulatory T cells with COPD 429

Vol. 66(4): 426 - 435, 2025

relevant kit (Cat. No. 17-1140-02, GE Health-

care Life Sciences, USA) to isolate peripheral

blood mononuclear cells (PBMCs). Then, the

resulting cell suspension was incubated with

monoclonal antibodies against CD4-CD4-

fluorescein isothiocyanate (FITC) and CD25-

CD25-phycoerythrin (PE) (BD, USA), with

immunoglobulin G (IgG)-FITC and IgG-PE

as controls. Afterwards, the FAS-Calibur flow

cytometer (BD, USA) was employed to de-

tect CD4+ Treg cell count, CD25+ Treg cell

count, and CD4+CD25+ Treg cell count.

Pulmonary function test

The forced expiratory volume in one

second (FEV1) and forced vital capacity

(FVC) were determined with the HI-801 pul-

monary function tester (CHEST, Japan) on

the day of physical examination in the smok-

ing group and the healthy group and before

treatment in the COPD group, based on

which the FEV1/FVC value was calculated.

Statistical analysis

Statistical analysis was performed using

the SPSS 26.0 software. Measurement data

were expressed as mean ± standard devia-

tion ( ± s) and subjected to the t-test for

comparison between two groups and one-way

analysis of variance for comparison among

multiple groups. Count data were described

as [n (%)] and examined by the χ2 test. Spear-

man’s rank correlation analysis was conduct-

ed to explore the correlations between levels

of IL-17 and Treg subsets and pulmonary

function. Receiver operating characteristic

(ROC) curves were plotted, based on which

the association between IL-17 levels and

Treg subsets and the occurrence of COPD

was assessed. p<0.05 indicated that the dif-

ference was statistically significant.

RESULTS

Levels of IL-17 and Treg subsets

in the peripheral blood

The COPD group showed the high-

est IL-17 levels and the lowest CD4+ Treg

cell count, CD25+ Treg cell count, and

CD4+CD25+ Treg cell count in peripheral

blood, followed by the smoking group and

the healthy group (p<0.05) (Table 1).

Values of IL-17 and Treg subset levels in

the peripheral blood for association with

COPD occurrence

The areas under the ROC curves [AUCs,

95% confidence interval (95% CI)) of IL-17

level, CD4+ Treg cell count, CD25+ Treg cell

count, and CD4+CD25+ Treg cell count in

the peripheral blood and their combination

for associating with the occurrence of COPD

were 0.866 (0.813-0.920), 0.885 (0.833-

0.936), 0.799 (0.735-0.863), 0.773 (0.705-

0.840), 0.949 (0.919-0.979), respectively

(Table 2 and Fig. 1).

Table 1. Levels of IL-17 and Treg subsets in the peripheral blood.

Group n IL-17 level

(ng/L)

CD4+ Treg

cell count (%)

CD25+ Treg

cell count (%)

CD4+CD25+ Treg

cell count (%)

Healthy 90 13.26±3.84 31.57±4.52 4.53±0.85 3.68±0.75

Smoking 90 28.48±5.65a25.15±5.68a3.21±0.79a3.05±0.64a

COPD 90 38.12±6.87ab 16.58±4.74ab 2.34±0.67ab 2.34±0.71ab

F451.893 203.182 182.842 82.202

p <0.001 <0.001 <0.001 <0.001

ap<0.05 vs. the healthy group, bp<0.05 vs. the smoking group.

Data is expressed as mean ± standard deviation. One-way analysis of variance was used to compare multiple groups.

Chronic obstructive pulmonary disease (COPD).

430 Chen et al.

Investigación Clínica 66(4): 2025

Levels of IL-17 and Treg subsets in the

peripheral blood of COPD patients with

different severities

The IL-17 level in the peripheral blood

was the highest in the severe group, fol-

lowed by the moderate group and the mild

group, while the CD4+ Treg cell count,

CD25+ Treg cell count, and CD4+CD25+

Treg cell count were the highest in the mild

group, followed by the moderate group and

the severe group (p<0.05) (Table 3).

Pulmonary function in COPD patients

with different severities

The FEV1, FVC, and FEV1/FVC were the

highest in the mild group, moderate in the

moderate group, and the lowest in the se-

vere group (p<0.05) (Table 4).

Correlations of IL-17 and Treg subset

levels in the peripheral blood with

pulmonary function

The results of the Spearman’s rank cor-

relation analysis showed that the IL-17 level

was negatively correlated with FEV1, FVC,

and FEV1/FVC (r<0, p<0.05).

Table 2. Values of IL-17 and Treg subset levels in the peripheral blood

for predicting COPD occurrence.

Indicator Area under

the curve

Standard

error

Optimal cut-off

value p 95% confidence

interval

IL-17 0.866 0.027 32.584ng/L <0.001 0.813-0.920

CD4+Treg 0.885 0.026 20.025% <0.001 0.833-0.936

CD25+Treg 0.799 0.033 2.684% <0.001 0.735-0.863

CD4+CD25+Treg 0.773 0.034 2.641% <0.001 0.705-0.840

Combination 0.949 0.015 - <0.001 0.919-0.979

Chronic obstructive pulmonary disease (COPD).

Fig. 1. ROC curves of IL-17 and Treg subset levels in the peripheral blood for predicting Chronic obstructive pul-

monary disease (COPD) occurrence.

ROC curve

Sensitivity

1– specificity

IL-17

CD4+Treg

Reference line

CD24+CD25+Treg

Unite

CD25+Treg

Curve source

Correlations of interleukin-17 and regulatory T cells with COPD 431

Vol. 66(4): 426 - 435, 2025

In contrast, the CD4+ Treg cell count,

CD25+ Treg cell count, and CD4+CD25+ Treg

cell count were positively correlated with

FEV1, FVC, and FEV1/FVC (r>0, p<0.05)

and negatively correlated with IL-17 level

(r<0, p<0.05) (Table 5).

DISCUSSION

COPD is characterized by airway wall

thickening, accumulation of inflammatory

mucus, and infiltration of adaptive and in-

nate immune cells. Among them, CD4+ T

lymphocytes play a critical role in the patho-

genesis of COPD 9,10. Under normal condi-

tions, the balance of Th subsets helps main-

tain immune homeostasis, but in COPD, this

balance is disturbed, with overactivation of

Th17 cells and reduction of Treg cells 11.

Th17 cells secrete IL-17 and IL-22,

which recruit neutrophils and other inflam-

matory cells, thus amplifying airway inflam-

mation. IL-17 also stimulates macrophages,

dendritic cells, and fibroblasts to release

chemokines, pro-inflammatory cytokines,

and proteolytic enzymes, all of which con-

tribute to tissue damage and a decline in

pulmonary function 12-14. Elevated IL-17 fur-

ther promotes neutrophil and macrophage

infiltration, exacerbating airway injury 15.

Smoking additionally aggravates airway ob-

struction by inducing epithelial damage,

mucosal gland hypertrophy, and ciliary dys-

function, and it promotes Th17 proliferation

and IL-17 release 16.

In contrast, Treg cells play a protective

role by suppressing autoreactive T cells and

excessive immune activation 17. CD4+CD25+

Table 3. Levels of IL-17 and Treg subsets in the peripheral blood

of COPD patients with different severities.

Group n IL-17 level

(ng/L)

CD4+ Treg

cell count (%)

CD25+ Treg

cell count (%)

CD4+CD25+ Treg

cell count (%)

Mild 30 31.25±5.58 20.35±4.65 3.02±0.68 2.89±0.52

Moderate 42 37.85±6.85a 14.25±4.58a 2.03±0.59a 2.11±0.47a

Severe 28 45.10±5.87ab 10.11±3.68ab 1.24±0.49ab 1.26±0.57ab

F35.865 40.607 65.732 72.701

p <0.001 <0.001 <0.001 <0.001

ap<0.05 vs. the mild group, bp<0.05 vs. the moderate group. Chronic obstructive pulmonary disease (COPD).

Data is expressed as mean ± standard deviation. One-way analysis of variance was used to compare multiple groups.

Table 4. Pulmonary function in COPD patients with different severities.

Group n FEV1 (L) FVC (L) FEV1/FVC (%)

Mild 30 1.89±0.56 3.58±0.71 63.25±6.58

Moderate 42 1.49±0.62a 2.95±0.68a 57.48±5.59a

Severe 28 1.15±0.49ab 2.32±0.65ab 51.74±6.68ab

F12.343 24.802 24.885

p <0.001 <0.001 <0.001

ap<0.05 vs. the mild group, bp<0.05 vs. the moderate group. Data is expressed as mean ± standard deviation.

One-way analysis of variance was used to compare multiple groups. Forced vital capacity (FVC), Forced expiratory

volume in one second (FEV1), Chronic obstructive pulmonary disease (COPD).

432 Chen et al.

Investigación Clínica 66(4): 2025

Treg cells inhibit effector T-cell prolifera-

tion through IL-2 and IFN-γ suppression

and TGF-β–mediated pathways 18. In the

present study, comparisons were carried

out on the CD4+ Treg cell count, CD25+

Treg cell count, and CD4+CD25+ Treg cell

count among the three groups. The results

showed that the CD4+ Treg cell count,

CD25+ Treg cell count, and CD4+CD25+

Treg cell count were lowest in the COPD

group, moderate in the smoking group, and

highest in the healthy group, suggesting

immunomodulatory dysfunction in COPD

patients and smokers, especially in the for-

mer. The CD4+ Treg cell count, CD25+ Treg

cell count, and CD4+CD25+ Treg cell count

were the lowest in the severe group, moder-

ate in the moderate group, and the highest

in the mild group. According to the Spear-

man’s rank correlation analysis, the CD4+

Treg cell count, CD25+ Treg cell count, and

CD4+CD25+ Treg cell count were positively

correlated with FEV1, FVC and FEV1/FVC,

demonstrating that the level of Treg sub-

sets can reflect the condition of COPD pa-

tients to a certain extent, and that patients

with a high expression of Treg subsets often

have good pulmonary function. This is be-

cause CD4+ Treg cells, CD25+ Treg cells,

and CD4+CD25+ Treg cells can impede

the production of Th1 and Th17 cells via

the autocrine transforming growth factor-β

(TGF-β) pathway. However, in cases of low

Treg expression, they cannot suppress in-

flammatory cytokines, leading to an im-

balance between Th1 and Th2 cell counts.

Accordingly, IL-4 expression will be further

suppressed, and IL-17 and IFN-γ levels will

be increased, resulting in persistently high

immune responses, damaging lung and air-

way tissues, weakening pulmonary function,

and thereby inducing COPD 19,20.

Furthermore, the results of the pres-

ent study also showed that the CD4+ Treg

cell count, CD25+ Treg cell count, and

CD4+CD25+ Treg cell count displayed nega-

tive correlations with IL-17 level, signifying

that the down-regulation of Treg subsets

and the high expression of IL-17 (a charac-

teristic inflammatory factor of Th17 cells)

will disrupt the balance between Th17 cell

count and Treg cell count, increase air-

way secretions and airway inflammatory

responses, affect lung ventilation func-

tion, and further damage pulmonary func-

tion and lung tissues. The balance between

Th17 cell count and Treg cell count should

be maintained by taking appropriate mea-

sures, thus preventing COPD or its exacer-

bation 21.

Our study provides novel insights into

several aspects. First, our cohort included

exclusively COPD patients without asthma,

ensuring disease specificity. Second, we si-

multaneously evaluated IL-17 and Treg sub-

sets, and demonstrated that their combined

Table 5. Correlations of IL-17 and Treg subset levels in the peripheral blood with pulmonary function.

Indicator Coefficient IL-17 FEV1FVC FEV1/FVC

IL-17 r- -0.415 -0.535 -0.552

p- <0.001 <0.001 <0.001

CD4+Treg r-0.536 0.428 0.585 0.597

p<0.001 <0.001 <0.001 <0.001

CD25+Treg r-0.589 0.448 0.597 0.603

p<0.001 <0.001 <0.001 <0.001

CD4+CD25+Treg r-0.645 0.487 0.615 0.637

p<0.001 <0.001 <0.001 <0.001

Forced vital capacity (FVC), Forced expiratory volume in one second (FEV1).

Correlations of interleukin-17 and regulatory T cells with COPD 433

Vol. 66(4): 426 - 435, 2025

imbalance (increased IL-17 and decreased

Treg levels) was more strongly associated

with COPD severity than IL-17 alone. Third,

by stratifying patients by GOLD grade, we

revealed dynamic changes in these immune

markers across disease progression. Collec-

tively, these findings highlight the impor-

tance of the IL-17/Treg axis in COPD immu-

nopathogenesis.

However, several limitations should

be recognized. One limitation is that de-

tailed information on inhaled corticoste-

roid (ICS) use was not systematically col-

lected for all COPD patients. Since ICS

therapy may influence cytokine profiles,

such as reducing IL-17 levels or affecting

Treg responses, its impact on our findings

cannot be ruled out. Future studies with

more complete treatment records and

subgroup analyses are needed to address

this. Another limitation is that we did not

measure eosinophil and neutrophil counts

or their relationship with IL-17 levels. Be-

cause these cells are key players in airway

inflammation, future research should in-

clude them to better understand the con-

nection between IL-17 and innate immune

responses in COPD.

In conclusion, IL-17 is upregulated,

and Treg subsets are downregulated in

COPD, with their imbalance closely linked to

impaired lung function and disease severity.

The combined detection of IL-17 and Treg

subsets may thus offer more informative bio-

markers for evaluating COPD progression.

Funding

This study was financially supported

by the Applied Basic Research Project of

Changzhou Science and Technology Bureau

(No. CJ20209030).

Conflict of interest

The authors confirm that the content

of this article has no conflict of interest.

ORCID number of authors

• Jun Chen (JC):

0009-0000-7755-4448

• Tingting Zhao (TZ):

0009-0003-7801-2757

• Yingying Gao (YG):

0009-0005-1514-8846

• Zizhou Zhang (ZZ):

0009-0006-9648-3386

Contributions of each author

JC and ZZ designed this study and pre-

pared the manuscript; TZ and YG conducted

this study and analyzed the data. All authors

have approved the submission and publica-

tion of this paper.

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