Interleukin-1 Beta (IL-1<i>β</i>) in the Peripheral Blood of Dogs as a Possible Marker for the Detection of Early Stages of Inflammation

doi:10.4236/ojvm.2013.37049

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Open Journal of Veterinary Medicine, 2013, 3, 302-308

Published Online November 2013 (http://www.scirp.org/journal/ojvm)

http://dx.doi.org/10.4236/ojvm.2013.37049

Open Access OJVM

Interleukin-1 Beta (IL-1β) in the Peripheral Blood

of Dogs as a Possible Marker for the Detection of

Early Stages of Inflammation

Christian Prachar1, Franz-Josef Kaup2, Stephan Neumann1*

1Small Animal Clinic, Institute of Veterinary Medicine, University of Goettingen, Goettingen, Germany

2German Primate Centre, Goettingen, Germany

Email: *[email protected]

Received August 24, 2013; revised September 24, 2013; accepted September 30, 2013

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Background: Cytokines are mediators of disease. Expression levels in the blood could be of clinical relevance. Objec-

tive: Aim of this study was to show if serum levels of IL-1β could be of any clinical relevance concerning dogs. IL-1β

was measured in serum samples of healthy dogs to find a reference range for healthy individuals. Measurements of

IL-1β should show if this substance was a possible marker for early stages of inflammation. Therefore, a possible rela-

tion between serum levels and grades of leukocytosis was analyzed. Methods: IL-1β concentrations in the blood were

assessed by the use of a human enzyme linked immunosorbent assay (ELISA). 39 dogs with different inflammatory

diseases were analyzed to figure out if there was a correlation between IL-1β serum levels and the number of leukocytes

in peripheral blood. The control group consisted of 16 healthy dogs. Results: about half of the samples IL-1β were de-

tected. Most of the patients showed no detectable amounts of IL-1β. The IL-1β levels measured in the serum were stable

for at least nine weeks when stored at −20˚C. The patients tested positively on IL-1β had mostly lower-grade leukocy-

tosis compared to those who had no IL-1β in serum. All the dogs which were suffering from disease but still had no

traceable IL-1β, showed a leukocytosis as a common symptom. Conclusion: This study showed that IL-1β could be-

come an interesting marker for the detection of early stages of inflammation when leukocytosis does not yet appear in

peripheral blood. Nonetheless, the possible use in diagnosis is restricted. This is due to the fact that there are only low

amounts of IL-1β to be detected in the serum, even concerning patients are suffering from disease.

Keywords: IL-1β; Interleukin-1 Beta; ELISA; Dog

1. Introduction

Besides TNF-α and IFN-γ, Interleukin-1 plays a central

role in acute and chronic inflammation, both locally and

systemically. There are two subtypes which are IL-1α

and IL-1β. Both subtypes are mainly produced by mo-

nocytes, macrophages, endothelial cells and fibroblasts

[1]. Although the two subtypes only share a sequence

homology of 25% [2], they bind to the same receptor on

T-cell-surface [3].

Both subtypes consist of precursor molecules with a

molecular size of 31 kDa, which are split by converting

enzymes. The mature IL-1β-molecule has a size of 17

kDa and consists of the mature IL-1β molecule and a

pro-segment. The cell releases a combination of these

molecules along with a prepro-IL-1β[1].

IL-1 acts as a pyretic in the body. This stimulates

lymphocyte activity and the production of acute phase

proteins in the liver as well as the release of collagenases

and prostaglandins [4]. As IL-12, IL-1 induces

IFN-γ-secretion by natural killer cells, which results in an

IFN-γ-induced activation of macrophages. IL-1α is only

produced by monocytes and macrophages and is in-

volved in different immunological processes, especially

maintaining the dermal immunological barrier. IL-1β is

also produced by astrocytes, oligodendroglia, adrenal

cortical cells, platelets, osteoblasts and different kinds of

T-cells. Because IL-1β is a hormone-like substance, it is

like many other cytokines not stored in cells and tissue.

This makes it difficult to detect IL-1β in cell culture su-

pernatants, but it leads to acceptable results measuring

*Corresponding author.

C. PRACHAR ET AL. 303

IL-1β-levels in blood serum samples [5].

Many different kinds of cells have receptors to bind

IL-1β. There are two different types of receptors for IL-1:

The IL-1-receptor I (IL-1 RI) and the IL-1-receptor II

(IL-1 RII). In addition to these, there also exists a non-

binding receptor accessory protein (IL-1 RAcP). Signal-

ing is only mediated by IL-1 RI together with IL-1 RAcP,

which interacts only with IL-1 RI in complex formation

with IL-1 [1].

IL-1β is one of the most important inflammatory cyto-

kines. IL-1β precipitates acute attacks of both local and

systemic inflammation. It also contributes to several

chronic diseases. Furthermore it is also known for medi-

ating the acute phase response to infection, injury and

immune challenge [6]. For example IL-1β induces the

production of IL-6, but IL-6 inhibits the expression of the

other pro-inflammatory cytokine. Besides TNF-α, IL-1β

is one of the first pro-inflammatory cytokines increasing

in inflammation, which is important because every cyto-

kine plays a precise role in regulating the expression of

other cytokines [7].

In early stages acute inflammation is mediated by

granulocytes, while chronic inflammation is mediated by

mononuclear cells such as monocytes and lymphocytes.

Neutrophil granulocytes are those of the first-responders

of inflammatory cells and they migrate towards the site

of inflammation. Within the first 6 to 12 hours of in-

flammatory reaction, the number of leukocytes increases

and mature so-called segmented neutrophil granulocytes

are set free by the bone marrow. In case of injury, neu-

trophils emigrate from blood vessels into the damaged

tissue within a few minutes. Bacterial infections, tumors

and many other different diseases can lead to inflamma-

tion too.

Over the past years many veterinary medical studies

were made in order to analyze the expression of IL-1β in

different tissues of the canine body [8-10]. Still only a

few measurements were implemented on blood plasma or

serum samples [11]. So far, no studies were made re-

garding a correlation between IL-1β serum levels in dogs

suffering from different diseases.

The cause for this observation was to find out if IL-1β

can be detected in serum of dogs and so it may become a

useful diagnostic marker in veterinary medicine. As

mentioned above, IL-1β acts as one of the early pro-in-

flammatory cytokines. It was interesting to see if there

was a connection between increased levels of IL-1β and

different ones which meanwhile established inflamma-

tory markers like the number of leukocytes and neutro-

phil granulocytes.

2 Material and Methods

2.1. Animals

Altogether serum levels of 39 dogs were measured. 15

individuals were crossbreed while 24 were breed dogs.

Most frequent breeds were German shepherd 3), Boxer

2), Rhodesian Ridgeback 2), Golden Retriever 2) and

Beagle 2). The control group consisted of 16 healthy

individuals. The study was made according to the Ger-

man Animal Welfare Act.

Serum was isolated and aliquoted four times. The first

time point was set to the time right after the isolation.

The remaining three aliquots were frozen down immedi-

ately at ≤−20˚C. After 3, 6 and 9 weeks concentrations of

IL-1β were measured.

The number of leukoctyes was measured by volume

impedance with the Abbott Cell-Dyn® 3700 Haematol-

ogy Analyzer (Abbott GmbH & Co KG, Wiesbaden/Ger-

many).

2.2. ELISA

We used an ELISA developed for the quantitative deter-

mination of human IL-1β concentrations in serum (Quan-

tikine® ELISA, catalog number DLB50, R & D Systems,

Minnesota/USA). The genetic sequence homology of

76.4% in both human and canine IL-1β [12] made it pos-

sible to use a human ELISA to measure serum levels of

IL-1β in canine blood samples.

The measurement ofIL-1β went according to manu-

facturer’s recommendation. To determine the optical

density of each well, a microplate reader set to 450 nm

wave length was used.

The dogs tested for serum levels of IL-1β were pa-

tients of the Small Animal Clinic of Georg-August-Uni-

versity in Goettingen/Germany. Depending on theirtype

of disease, diagnosis was confirmed by general examina-

tion, blood and urine tests, X-ray, ultrasound diagnostics,

computed tomography, endoscopy, diagnostic laparo-

scopy and histopathological tests. In this study, the most

severe diagnoses were mentioned. These were confirmed

for a few patients who suffered from different diseases

simultaneously.

Altogether, serum levels of 39 dogs with different dis-

eases were measured. The control group consisted of 16

healthy individuals. The study was made according to the

German Animal Welfare Act.

Statistical analysis was made with SPSS software. Due

to the fact that both concentrations of IL-1β and the

number of leukocytes were not normally distributed

(Kolmogorov-Smirnov-test p < 0.001), non-parametric

methods were used for statistical analysis.

Blood samples from the dogs were taken to assess the

stability of IL-1β when stored at ≤−20˚C Celsius. Serum

was isolated and aliquoted into four samples. The first

time point was set to the time right after the isolation.

The remaining three aliquots were frozen down immedi-

ately at ≤−20˚C.

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C. PRACHAR ET AL.

304

Measurements of IL-1β took place at the day of the

blood taking and after 3, 6 and 9 weeks.

2.3. Results

2.3.1. Storage

Our analysis showed that IL-1β in serum can be stored at

≤−20˚C Celsius for at least nine weeks. Even beyond that

time there was no obvious decrease of IL-1β found in the

samples.

2.3.2. IL-1β in Healthy Dogs

Significantly higher serum levels of IL-1β were detected

in patients suffering from disease compared to those of

healthy controls (chi-square test = 0.003) (Figure 1). In

the healthy control group only two out of 16 dogs were

tested positively on IL-1β. Yet, they were both in very

low concentrations (0.11 and 1.04 pg/ml). 14 dogs

(87.5%) showed no detectable amount of IL-1β in their

serum.

2.3.3. IL-1β in Dogs with Different Internal Diseases

Even though most of the serum levels werevery low,

many of the patients showed positive results (22 out of

39 dogs). IL-1β serum concentrations were measured in

39 dogs with different internal diseases (Table 1), in-

cluding non-neoplastic diseases, benign tumors and ma-

lignant neoplasia. 24 of the 39 dogs were bitches, while

15 were male dogs. 7 out of the 15 male dogs showed no

detectable IL-1β in serum (46.6%), and so did 12 of the

24 bitches (50%). The age of the dogs with detectable

IL-1β in their serum lay between 3.5 and 14.5 years (me-

dian 9.2, mean 10.0).

The highest level of IL-1β was detected in the serum

of a dog with an adenoma of the hepatoid glands (64.71

pg/ml). This amount was significantly higher than those

Figure 1. IL-1β in the serum of dogs with different diseases

compared to healthy controls. Significantly higher serum

levels were found in the group of dogs with different dis-

eases compared to the healthy control group.

of all the other dogs with detectable amounts of IL-1β

(Figure 2).

2.3.4. IL-1β Serum Levels and Leukocytosis

A number of leukocytes >12.000 K/µl was stated leuko-

cytosis. There was no connection found between IL-1β

serum levels and leukocytosis (Figure 3). Noticeable is

the fact that all dogs with no detectable amount of IL-1β

in peripheral blood showed a leukocytosis (17 out of 17,

Table 2). 14 of the dogs with leukocytosis showed in-

creased levels of neutrophil granulocytes.

Two of the healthy individuals had very low serum

levels of 0.11 and 1.04 pg/ml withoutshowing the indica-

tion of a leukocytosis.

3. Discussion

In human medicine, many studies were conducted to

prove the importance of IL-1β in inflammatory reactions

of the body. Yet, in many cases they appear only for a

short period of time in acute diseases as well as in

chronic diseases with acute exacerbations. In one study

an experimentally induced endotoxin shock in dogs

based on the intravenous application of purified lipopo-

lysaccharides from Escherichia coli led to increased

IL-1-activity within the first 30 to 60 minutes with its

peak after 90 minutes. During 6 to 24 hours after appli-

cation, IL-1 was hardly detectable in blood [13]. Even in

severe systemic inflammatory diseases, levels of free

IL-1β are often undetectable, especially in peripheral

blood.

Within the last few years, most of the studies were

based on analyzing increased expression of IL-1β recep-

tors in different body tissue. This was performed espe-

cially by histopathological analyzes of tissues which

were affected by inflammatory reactions, as mentioned

above.

Measurement of IL-1β in serum or plasma in medical

diagnosis isapplied in human medicine. The reference

range forIL-1β concerninghumans is stated with <5

pg/ml.

Some diseases go along with increased serum levels of

IL-1β. In healthy patients, the detectable amounts of

IL-1β are ranging around the bottom line. However,

some studies led to different results. A study regarding

serum levels of different cytokines in patients with pri-

mary biliary cirrhosis, in which serum levels of IL-1β

were ranged from 170 to 540 pg/ml in the healthy control

group serves as an example [14].A correlation was found

between IL-1β in serum and the severity of diseases li-

keLeishmaniasis [15] or SLE, especially with a Lupus

nephritis [16]. Furthermore there was an increased IL-1β

activity found in patients with sepsis [17], traumatic

neuronal injury [18] and arteriosclerosis [19]. One study

showed that IL-1β also is involved in the aging process

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C. PRACHAR ET AL.

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305

Table 1. List of diseases of dogs tested positively on IL-1β.

Diagnosis IL-1β [pg/ml]

1) Adenoma of the hepatoid glands 64.71

2) Haemangiosarcoma of the spleen 4.7

3) Chronic renal failure, anaemia 4.7

4) Malignant mesenchymal dermal tumor 3.56

5) Cystic carcinoma of the mamma and tubular adenoma 2.9

6) Haemangiosarcoma of the spleen 2.53

7) Steatonecrosis with fibrosingsteatitis, pancreatitis 2.5

8) Lipoma 1.75

9) Borreliosis, anaplasmosis, high anti-thrombocyte antibody titer 1.33

10) Prostate carcinoma 0.82

11) Renal adenocarcinoma 0.75

12) Pyelonephritis, haemangiosarcoma of the spleen 0.65

13) Haemorrhagic liver necrosis 0.61

14) Retrobulbar round cell tumor (malignant lymphoma) 0.6

15) Oral malignant melanoma 0.53

16) Cystic granulosa cell tumor, leiomyoma of the cervix 0.51

17) Cystitis caused by struvituroliths 0.49

18) Gingivitis and stomatitis 0.29

19) Chronic renal failure 0.25

20) Solid to papillary carcinoma of the mamma 0.18

21) Pyometra 0.06

22) Purulent mastitis 0.03

Figure 2. IL-1β in the serum of dogs with different diseases

compared to healthy controls with statistical outlier in the

group of dogs with disease: 64.71 pg/ml. As you can see this

dog in the diseased group showed a serum level which was

noticeably higher than those of all other dogs.

Figure 3. Numbers of leukocytes in dogs with detectable

serum levels of IL-1β. It is noticeable, that all the dogs

without free IL-1β (n = 17) showed a leukocytosis, while

most of the dogs with measurable IL-1β had a normal leu-

kocyte count (see above in Table 2).

[20]. tive pulmonary disease. The most important agent is Ca-

nakinumab which is a human monoclonal antibody

against IL-1β and was developed by Novartis [21].

In human medicine, the blocking effect of IL-1β is

meanwhile used therapeutically. An example for this is

the treatment of rheumatoid arthritis and chronic obstruc- So far no comparable studies on IL-1β in dogs were

C. PRACHAR ET AL.

306

Table 2. Comparison of IL-1β serum levels of dogs with and without a leukocytosis (number of leukocytes >12.000 K/µl).

Number of leukocytes >12.000 K/µl

not found found total

IL-1β [pg/ml] negative Dogs 0 17 17

positive Dogs 10 12 22

Total Dogs 10 29 39

made. There are no copious studies for serum levels of

IL-1β in healthy or ill dogs, especially not regarding the

measurement of serum levels. Furthermore, blocking

IL-1β has no relevance in treating acute or chronic in-

flammatory diseases in veterinary medicine.

Since there are no reliable reference ranges for serum

levels of IL-1β concerning dogs, one aim of our study

was to find out if IL-1β can be detected in the serum of

healthy dogs. For the possible routinely use in veterinary

medicine, it was furthermore relevant to find out if mea-

surements of IL-1β serum levels are diagnostically con-

clusive. This is due to the fact that blood analyzes are

less invasive and can lead to faster results than other

tests.

4. Conclusions

Results of our study show that concerning healthy dogs,

IL-1β mostly can’t be detected at all or only in very low

concentrations in ranges of <1 pg/ml.

Our study should show if IL-1β was a possible marker

for inflammatory reactions concerning dogs which suf-

fered from different internal diseases. The outcome of

this study leads to the assumption that IL-1β in serum

increases in the majority of cases in early stages of in-

flammation, respectively during acute exacerbations of

disease. In progressed stages when leukocytosis appears

in peripheral blood, the free IL-1β in serum decreases.

We found evidence for this because all dogs without de-

tectable IL-1β (n = 17) in blood serum showed a leuko-

cytosis. Though in this study there was no statistical sig-

nificance finding between IL-1β serum levels and the

number of leukocytes, it is remarkable that all the pa-

tients with no detectable IL-1β in their serum showed a

leukocytosis.

In healthy individuals there is hardly any IL-1β finding

in peripheral blood. Most of the already implemented

studies are mainly conducted in human medicine and

show that healthy individuals have IL-1β serum concen-

trations below the minimum detectable dose. Further-

more, even patients suffering from inflammatory diseases

seldom show IL-1β serum levels above the minimum de-

tectable dose, as described above. In this study only two

healthy dogs were tested positively on IL-1β, but only in

very low concentrations.

The dogs in this study suffered from many different

diseases. Only two diseases appeared in more than one

dog (haemangiosarcoma of the spleen, n = 2, and chronic

renal failure, n = 2). Those diseases led to different con-

centrations of IL-1β (haemangiosarcoma 2.53 and 4.7

pg/ml, chronic renal failure 0.25 and 4.7 og/ml) which

are hardly comparable. Further studies on a larger group

of dogs suffering from the same disease should follow.

The highest serum levels were found in dogs with very

different diseases: the highest amount of IL-1β was

found in a dog with benign tumor (64.71 pg/ml), fol-

lowed by one with a malignant neoplasia (4.7 pg/ml) and

one with chronic renal failure (4.7 pg/ml). It is noticeable

that no other dogs in the diseased group (n = 39) reached

a serum level near the highest one.

Even if IL-1β increases in different periods of progress

of the disease, there seem to be no steadily high serum

levels. Follow-up measurements during the progress of

disease (whether treated or not) could indicate if different

stages of disease are associated with the increase or de-

crease of IL-1β in serum. This may be caused by the fact

that detectable amounts of IL-1β appear very early in

inflammation. As soon as inflammation begins, the

number of neutrophil granulocytes increases. Stored neu-

trophils are set free from the bone marrow and after that

new neutrophils are produced.

Since IL-1β is a very important pro-inflammatory cy-

tokine with many different functions regarding the be-

ginning and the progression of inflammation, it could

become an interesting diagnostic marker even in veteri-

nary medicine.

We assume that increased IL-1β can be found mainly

in a time when already no leukocytosis appears in blood.

Followed by leukocytosis with mostly banded neutro-

phils, increasing IL-1β could be used as an indicator for

the early pro-inflammatory immune response. Our study

suggests that measurement of IL-1β in the serum of dogs

suffering from disease could become a useful addition to

the measurement of the leukocyte count, which is rou-

tinely used in veterinary medicine since decades. An-

other useful marker for inflammation is the C-reactive

protein (CRP). Further studies should be conducted to

find out if there is a direct relation between the number

of leukocytes or serum levels of CRP and the detectable

amount of IL-1β in peripheral blood. Furthermore it

could be interesting to look at the neutrophil granulo-

cytes in detail, because Seite: 2 new cells must be pro-

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C. PRACHAR ET AL. 307

duced when the stored and mature neutrophils are used

up. This can be seen in blood analyzes when the amount

of the so-called banded neutrophils increases compared

to the mature and segmented neutrophils.

Detectable amounts of IL-1β are correlated with any

inflammatory reaction. Still, there appears to be a very

limited period of time in which free IL-1β can be de-

tected in the serum. This unfortunate fact is the reason

why IL-1β is not used in common diagnosis.

Diagnostic techniques with a higher sensitivity like the

ones with lower concentration ranges may be more ap-

propriate for measurements of IL-1β in the serum. Even

if measurements with a human ELISA showed good re-

sults, a specific ELISA for canine IL-1β could lead to

better results.

Further studies on a larger population could find evi-

dence that IL-1β perhaps is a useful marker for early

stages of inflammation, comparable to the fact that the

grade of leukocytosis is a good parameter to assess the

stage of inflammation.

REFERENCES

[1] C. A. Dinarello, “Biologic Basis for Interleukin-1 in Dis-

ease,” Blood, Vol. 87, No. 6, 1996, pp. 2095-2147.

[2] J. L. Telford, G. Macchia, A. Massone, V. Carinci, E.

Palla and M. Melli, “The Murine Interleukin 1 Beta Gene:

Structure and Evolution,” Nucleic Acids Research, Vol.

14, No. 24, 1986, pp. 9955-9963.

http://dx.doi.org/10.1093/nar/14.24.9955

[3] P. L. Kilian, K. L. Kaffka, A. S. Stern, D. Woehle, W. R.

Benjamin, T. M. Dechiara, U. Gubler, J. J. Farrar, S. B.

Mizel and P. T. Lomedico, “Interleukin 1 Alpha and In-

terleukin 1 Beta Bind to the Same Receptor on T Cells,”

The Journal of Immunology, Vol. 136, No. 12, 1986, pp.

4509-4514.

[4] C. A. Meyers, K. O. Johanson, L. M. Miles, P. J. McDe-

vitt, P. L. Simon, R. L. Webb, M. J. Chen, B. P. Holskin,

J. S. Lillquist and P. R. Young, “Purification and Charac-

terization of Human Recombinant Interleukin-1 Beta,”

The Journal of Biological Chemistry, Vol. 262, No. 23,

1987, pp. 11176-11181.

[5] S. K. Durum, J. A. Schmidt and J. J. Oppenheim, “Inter-

leukin 1: An Immunological Perspective,” Annual Review

of Immunology, Vol. 3, No. 1, 1985, pp. 263-287.

http://dx.doi.org/10.1146/annurev.iy.03.040185.001403

[6] C. A. Dinarello, “Interleukin-1 and the Pathogenesis of

the Acute-Phase Response,” The New England Journal of

Medicine, Vol. 311, No. 22, 1984, pp. 1413-1418.

http://dx.doi.org/10.1056/NEJM198411293112205

[7] F. Ceciliani, A. Giordano and V. Spagnolo, “The Syste-

mic Reaction during Inflammation: The Acute-Phase Pro-

teins,” Protein and Peptide Letters, Vol. 9, No. 3, 2002,

pp. 211-223.

http://dx.doi.org/10.2174/0929866023408779

[8] A Grone, S. Fonfara and W. Baumgartner, “Cell Type-

Dependent Cytokine Expression after Canine Distemper

Virus Infectio,” Viral Immunology, Vol. 15, No. 3, 2002,

pp. 493-505.

http://dx.doi.org/10.1089/088282402760312368

[9] M. F. Rai, P. S. Rachakondaa, K. Manning, B. Vorwerk,

L. Brunnberg, B. Kohn, M. F. G. Schmidt, “Quantifica-

tion of Cytokines and Inflammatory Mediators in a Three-

Dimensional Model of Inflammatory Arthritis,” Cytoki ne,

Vol. 42, No. 1, 2008, pp. 8-17.

http://dx.doi.org/10.1016/j.cyto.2008.02.004

[10] J. Y. Yhee, C.-H. Yu, J.-H. Kim and J.-H. Sur1, “Effects

of T Lymphocytes, Interleukin-1, and Interleukin-6 on

Renal Fibrosis in Canine End-Stage Renal Disease,”

Journal of Veterinary Diagnostic Investigation, Vol. 20,

No. 5, 2008, pp. 585-592.

http://dx.doi.org/10.1177/104063870802000508

[11] K. K. Al’tsivanovich and V. N. Gurin, “Activity of Blood

Interleukin-1 in Dogs during Work Hyperthermia,” Bulle-

tin of Experimental Biology and Medicine, Vol. 110, No.

12, 1990, pp. 565-567.

[12] J. T. Soller, H. Murua-Escobar, S. Willenbrock, M.

Janssen, N. Eberle, J. Bullerdiek and I. Nolte, “Compari-

son of the Human and Canine Cytokines IL-1 (Al-

pha/Beta) and TNF-Alpha to Orthologous Other Mam-

malians,” Journal of Heredity, Vol. 98, No. 5, 2007, pp.

485-490.

http://dx.doi.org/10.1093/jhered/esm025

[13] T. Miyamoto, T. Fujinaga, K. Yamashita and M. Hagio,

“Changes of Serum Cytokine Activities and Other Pa-

rameters in Dogs with Experimentally Induced Endotoxic

Shock,” The Japanese Journal of Veterinary Research,

Vol. 44, No. 2, 1996, pp. 107-118.

[14] V. Barak, C. Selmi, M. Schlesinger, M. Blank, N. Ag-

mon-Levin, I. Kalickman, M. E. Gershwin and Y. Shoen-

feld, “Serum Inflammatory Cytokines, Complement Com-

ponents, and Soluble Interleukin 2 Receptor in Primary

Biliary Cirrhosis,” Journal of Autoimmunity, Vol. 33, No.

3-4, 2009, pp. 178-182.

http://dx.doi.org/10.1016/j.jaut.2009.09.010

[15] E. A. Fernandez-Figueroa, et al., “Disease Severity in

Patients Infected with Leishmania Mexicana Relates to

IL-1β,” PLOS Neglected Tropical Diseases, Vol. 6, No. 5,

2012, p. E1533.

[16] B. Brugos, Z. Vincze, S. Sipka, G. Szegedi and M. Zeher,

“Serum and Urinary Cytokine Levels of SLE Patients,”

Pharmazie, Vol. 67, No. 5, 2012, pp. 411-413.

[17] S. Papin, S. Cuenin1, L. Agostini1, F. Martinon1, S. Wer-

ner, H.-D. Beer, C. Grütter, M. Grütter and J. Tschopp,

“The SPRY Domain of Pyrin, Mutated in Familial Medi-

terranean Fever Patients, Interacts with Inflammasome

Components and Inhibits Proil-1β Processing,” Cell

Death and Differentiation, Vol. 14, No. 8, 2007, pp.

1457-1466. http://dx.doi.org/10.1038/sj.cdd.4402142

[18] S. M. Allan, P. J. Tyrrell and N. J. Rothwell, “Interleu-

kin-1 and Neuronal Injury,” Nature Reviews Immunology,

Vol. 5, No. 8, 2005, pp. 629-640.

http://dx.doi.org/10.1038/nri1664

[19] M. Kusuhara, K. Isoda and F. Ohsuzu, “Interleukin-1 and

Occlusive Arterial Diseases,” Cardiovascular & Hema-

tological Agents in Medicinal Chemistry, Vol. 4, No. 3,

Open Access OJVM

C. PRACHAR ET AL.

Open Access OJVM

308

2006, pp. 229-235.

http://dx.doi.org/10.2174/187152506777698335

[20] K. S. Kornman, “Interleukin 1 Genetics, Inflammatory

Mechanisms, and Nutrigenetic Opportunities to Modulate

Diseases of Aging,” The American Journal of Clinical

Nutrition, Vol. 83, No. 2, 2006, pp. S475-S483.

[21] C. A. Dinarello, A. Simon and J. W. van der Meer,

“Treating Inflammation by Blocking Interleukin-1 in a

Broad Spectrum of Diseases,” Nature Reviews Drug

Discovery, Vol. 11, No. 8, 2012, pp. 633-652.

http://dx.doi.org/10.1038/nrd3800