Changes of IL-1, TNF-Alpha, IL-12 and IL-10 Levels with Chronic Liver Failure

doi:10.4236/ss.2011.22015

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Surgical Science, 2011, 2, 69-72

doi:10.4236/ss.2011.22015 Published Online April 2011 (http://www.SciRP.org/journal/ss)

Changes of IL-1, TNF-Alpha, IL-12 and IL-10 Levels with

Chronic Liver Failure

Guowang Liu#, Kecheng Tang, Qian Li, Guiyu Yuan, Wukui Cao, Wei Lu*

Physician-in-Charge Tianjin Infectious Disease Hospital, Tianjin, China

E-mail: luwei1966@126.com, regulaly@163.com

Received January 6, 2011; revised January 25, 2011; accepted February 11, 2011

Abstract

[Aim] To investigate the action of cytokines in patients with chronic liver failure and to explore the roles of

cytokines in chronic liver failure. [Methods] Thirty-one patients with chronic liver failure admitted from

May 2006 to November 2009 were included. Thirty cases with mild to moderate chronic type B hepatitis

admitted concomitantly were regarded as control. IL-1, TNF-alpha, IL-12, IL-10 Levels in serum was the

factors to determine at clinical diagnosis and 2-week treatment. We analyzed levels of cytokines action in 31

chronic liver failure patients both at clinical diagnosis and 2-week treatment in comparison with control

group. [Results] We analyzed IL-1 level in death group at clinical diagnosis and 2-week treatment were sig-

nificant higher than in survival and control groups, furthermore it was also higher in survival group than in

control group. At clinical diagnosis, TNF-alpha level in death group was higher than that in control. How-

ever, there was no obviously difference between the death group and the survival group in TNF-alpha level.

With the progression of the disease, TNF-alpha level was remarkably risen in death group, but decreased in

survival group. IL-10 level was dramatically increased in death group, but no changed in survival group.

IL-12 level in death group was higher than in survival group, but lower than in control group. [Conclusions]

The levels of TNF-alpha, IL-1, IL-10 and IL-12 in patients with chronic liver failure was increased and the

increase of IL-10 is secondary to elevation of IL-12.

Keywords: Chronic Liver Failure, Cytokine, Hepatitis B

The pathogenesis of liver failure is very complicated,

which involves virus-induced primary immuno-patho-

logical damage, as well as cytokine-mediated effect.

Liver failure and multiple organ failure accompany with

the level changed in cytokines [1]. Each cytokine factor

has its own physiological function and interacts to each

others, which is also complicated to understand their

roles. Anti-inflammatory is the IL-10 main function. IL-1,

TNF-α are both inflammatory mediators. IL-12 has multi-

ple biological activities, including anti-viral, anti-tumor

and immunoregulation [2]. To an extent, IL-12 reflects

capabilities of human body in killing viruses. In this study,

we investigated the levels of IL-1, TNF-alpha, IL-12 and

IL-10 in serum in order to explore the roles of cytokines in

pathogenesis and progression of chronic severe hepatitis.

1. Subjects and Methods

1.1. Patients in this Study

Thirty-one patients (24 males, 7 females, average age of

40.08 ± 10.06 years, range 22-65 years) with chronic

liver failure admitted from May 2006 to November 2009

were included. Based on prognostic situation after one

month treatment, these patients were divided into two

groups: survival group and death group(survival group,

14 males, 4 females, average age of 39.22 ± 7.17 years,

range 30-55 years; death group, 10 males, 3 females,

average age of 41.23 ± 13.36 years, range 22-65 years).

All patients had hepatitis B virus infected, eleven cases

were in early stage and 20 cases in middle stage.

The other thirty cases with mild to moderate chronic

type B hepatitis admitted concomitantly were regarded as

control. This series contained 23 males and 7 females,

with the mean age of 40.28 ± 11.29 years (range 19-66

#Bachelor in Medicine, physician-in-charge Tianjin Infectious Disease

Hospital 300192 E-mail: [email protected]

*Corresponding author, Doctor of Philosophy in Medicine, professo

Tianjin Infectious Disease Hospital 300192

E-mail: [email protected]

70 G. W. LIU ET AL.

years). No combined infection with other hepatitis vi-

ruses were detected. Diagnosis were referred to the re-

vised “Diagnostic and treatment guidelines for liver fail-

ure” by Liver Failure and Artficial Liver Group ,Chinese

Society of Infectious Diseases, Chinese Medical Asso-

ciation; Severe Liver Diseases and Artifcial Liver Group,

Chinese Society of Hepatology, Chinese Medical Asso-

ciation [3]. There were no statistical differences in age,

sex ratio of number of early to middle stage patients

among survival group, death group and control group.

1.2. Therapy Methodologies

All chronic liver failure patients had to rest in bed and

had light diet. Combined therapy with hepatocyte

growth-promoting factors, sodium tanshinon IIA silate

and alprostadil were adopted. 22 cases in hepatic failure

group underwent non-bioartificial liver therapy including

plasma exchange and hemofiltration. Chronic hepatitis

patients had glutathione and licorice root preparation.

1.3. Observed Items

Cytokines: IL-1, TNF-alpha, IL-12, IL-10.

Blood samples were collected in the morning from

empty stomach clinical diagnosis and 2-week treatment

patients. Levels of serum IL-1, TNF-alpha, IL-12, IL-10

were measured by Luminex-100 bead-based fluorescence

flow cytometer (Luminex-100). Reagents come from

Becton, Dickinson and Company(Anti-XBP-1). Artificial

liver therapy was not taken in 24 hours before blood col-

lection.

1.4. Statistical Analysis Method

Data were analyzed by SPSS11.5 (Analysis of Variance).

2. Results

2.1. Comparison of Cytokine Levels at Clinical

Diagnosis Stage (Table 1)

IL-1, IL-10 and TNF-α level in death group was signify-

cantly higher than in the other two groups, and IL-1 level

in survival group was higher than that in control group

both at clinical diagnosis stage. IL-12 level in control

group was the lowest, and it was the highest in death

group at clinical diagnosis stage. IL-1, IL-12 levels were

differences among those three groups. TNF-α level in

control group was different from the other two groups

and no statistical differences between the other two

groups. IL-10 level in death group was different with the

other two groups and no statistical differences between

the other two groups.

2.2. Comparison of Cytokine Levels at 2-Week of

Treatment Stage (Table 2)

IL-1, IL-10 and TNF-α levels in death group was sig-

nificantly higher than in the other two groups, and IL-1

Table 1. Comparison of cytokine levels (pg/ml) at clinical diagnosis (mean  SD).

Items Survival group (18) Death group (13) Control group (30)F P

IL-1 86.00  26.38* 151.46  52.89* 40.96  18.10* 59.38 .000

TNF-α 53.50  73.49 87.76  91.38 14.80  4.74# 7.796 .001

IL-12 217.16  70.97* 289.38  89.17* 45.20  20.06* 99.767 .000

IL-10 28.91  16.75 247.46  192.05# 27.20  14.06 31.578 .000

Data was analyzed by q test. *: difference among in those three groups, #: difference with the other two groups, and no

statistical difference between the other two groups.

Table 2. Comparison of cytokine levels (pg/ml) at 2-week treatment (mean  SD).

Items Survival group (18) Death group (13) Control group (30)F P

IL-1 64.61  21.19* 82.14  20.85* 26.63  7.17* 58.956 0.000

TNF-α 28.88  26.20 283.92  586.06# 13.60  4.41 5.397 0.007

IL-12 175.33  57.08* 239.02  56.02* 31.23  17.39* 118.42 0.000

IL-10 49.88  157.46 346.50  313.71# 18.56  8.12 24.927 0.000

Data was analyzed by q test. *: difference among the three groups, #: difference from the other two groups, and no statis-

tical difference between the other two groups.

G. W. LIU ET AL.

level in survival group was higher than in control group.

IL-12 level in control group was the lowest, and it was

the highest in death group after 2-week treatment. IL-1,

IL-12 level are difference among those three groups.

TNF-α and IL-10 level in death group were different from

the other two groups and no statistical difference be-

tween the other two groups. IL-1 level at clinical diagnosis

stage was higher than after 2-week treatment, both in

death group and survival group.

3. Discussion

IL-1 helps body to fight against pathogenic microorgan-

isms and it is also one of non-specific defensive factors.

The results of at clinical diagnosis and 2-week treatment

stages were shown IL-1 level in death group was signify-

cantly higher than in the other two groups meanwhile, it

was the lowest in control group both at clinical diagnosis

and 2-week treatment stages, which suggested IL-1

might reflect the degree of inflammatory reaction and

serve as important index for prognosis of severe hepatitis.

Nevertheless, with the progression of the disease, IL-1

level at clinical diagnosis stage was higher than after

2-week treatment, both in death group and survival group.

This result implied that IL-1 secretion was decreasing

while the progression of Liver failure, therefore, resultes

in compromising of immunity. Those effectors, the pos-

sible reason, could be generated by a number of immu-

nocytes upon activation in early stage of disease,

whereas those effectors were decreasing indirectly due to

the apoptosis of immunocytes in the last stage.

TNF-α has a variety of biological effects, it is the

important factor in causing liver damage [4]. The level of

TNF-α was not only reflecting the capability of resisting

viral infection, but also associated with the immuno-

pathological to damage hepatocytes. At clinical diagnosis

stage, TNF-α level in severe hepatitis patients was sig-

nificantly higher than in control group, whereas there

was no statistical differences between death group and

survival group. With disease progressing, TNF-α level

was remarkably increasing in death group but decreasing

in survival group. After 2-week treatment, it was obvi-

ously higher in death group than in survival group. It was

suggested that changes of TNF-α could be the index of

the prognostic assessment, and TNF-α also reflected the

inflammation severity. Hepatic necrosis was reflected by

excessively high level of TNF-alpha, it might be one of

the important reasons of death.

IL-10, an important anti-inflammatory cytokine, par-

ticipated in principal negative feedback regulation in-

cluding inhibiting the generation of the inflammatory

factor and the colony stimulating factor in one hand and

suppressed the anti-viral immunity of the body in the

other hand. In this study, it shown anti-inflammatory

cytokines in severe hepatitis patients of death group were

dramatically raise, but not significantly changed in sur-

vival group, which suggested the increasing of anti-in-

flammatory cytokines in severe hepatitis patients espe-

cially at the last stage was an indirect indicator of severe

inflammation. And the raise of cytokine level could be

the result in immunity decreasing. The immunity of pa-

tients who suffered from severe hepatitis might be varied

at different stages of disease. At early stage, the inflame-

matory cytokines were releasing, and there is no in-

creasing in non-inflammatory factors. If the disease had

been well controlled, anti-inflammatory factors would be

no longer increasing. Otherwise, they would be signify-

cantly increasing to prevent the body from excessive

immune attack. Simultaneously, the immunity of patients

was declined.

IL-12 level in death group was higher than in survival

group both at clinical diagnosis and 2-week treatment

stage, and it was the lowest factor in control group,

which suggested there was intensive reaction for elimi-

nating pathogen at beginning of severe hepatitis, espe-

cially in heavy disease patients.

IL-1 could be amplified by the biological effect of

TNF-α, which could aggravate hepatic necrosis. Under

normal physiological condition, TNF-α and IL-1 could

be cleared by the liver. However, in case of liver failure,

endotoxin could activate macrophages, which could im-

pair the liver’s capability of eliminating cytokines. Thus,

TNF-α and IL-1 were the directly factors to develop of

liver failure. In our study, IL-10 raising did not suppress

the IL-12 increasing. In this study, it had shown IL-10

raising might be caused by increasing of IL-12, it might

be a compensatory response, which might prevent body

from excessive immunological damage. In addition, the

results of IL-10 in our study was different from Yumoto

E results [5]. We need more samples for the further

study.

4. References

[1] H. Isoniemi, A. M. Koivusalo, H. Repo and et a1. “The

Effect of Albumin Dialysis on Cytokine Levels in Acute

Liver Failure and Need for Liver Transplantation,”

Transplantation Proceedings, Vol. 37, No. 2, 2005, pp.

1088-1090. doi:10.1016/j.transproceed.2004.11.060

[2] Tao Wen and Hao Wu, “Research Progress of Inter-

leukin-12 and Its Application in Management of HIV In-

fection,” Foreign Medical Sciences (Epidemiology

Lemology Fascicle), Vol. 30, No. 5, 2003, pp. 271-274.

[3] J. Clin Hepatol, “Diagnostic and treatment guidelines for

liver failure,” Vol. 9, No. 6, 2006.

[4] R. F. Schwabe and D. A. Brenner, “Mechanisms of Liver

Injury Tnf-Alpha-Induced Liver Injury: Role of IKK,

72 G. W. LIU ET AL.

JNK, and ROS Pathways,” American Journal of Physi-

ology - Gastrointestinal and Liver Physiology, Vol. 290,

No. 4, 2006, pp. 583-589. doi:10.1152/ajpgi.00422.2005

[5] E. Yumoto, T. Higashi and K. Nouso, “Serum Gamma-

Interferon-Inducing Factor (Il-18) and IL-10 Levels in

Patients with Acute Hepatitis and Fulminant Hepatic

Failure,” Journal of Gastroenterology and Hepatology,

Vol. 17, 2002, pp. 285-294.

doi:10.1046/j.1440-1746.2002.02690.x