Yonago Acta medica 2003;46:29–34

Changes in Cytokines at Extreme Surroundings inAntarctica
Shinji Otani and Hiromitsu Kusagaya*
Division of Organ Surgical Oncology, Department of Surgery, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504 and *National Institute of Polar Research, Tokyo
173-8515 JapanWe evaluated the impact of the extreme environmental conditions at high altitudes inAntarctica on health from the viewpoint of cytokines. The subjects were 7 men who joined
an inland research party participating in the 40th Japanese Antarctic Research Expedition.
They underwent serial hematological examinations during the expedition for over 100
days at high altitudes (the highest point was 3810 m). The serum concentration of erythropoietin (EPO) increased promptly, indicating its usefulness for altitude adaptation. The
serum concentration of interleukin-6 (IL-6) increased at high altitudes, and showed 2 peaks.
Changes in IL-6 levels did not correlate with arterial oxygen tension, serum C-reactive
protein or EPO levels. Some psychological stress and various factors may be related toIL-6 levels. Since the subject who suffered bone fractures had a very high concentrationof IL-6 and his symptoms of mountain sickness were severer than the others, elevation ofIL-6 may be related with mountain sickness. All subjects remained in relatively good
health for 3 months. It is thought that the human body can protect itself against extreme
surroundings in Antarctica.
Key words: Antarctica; cytokine; high altitude; interleukin-6; mountain sickness

The average altitude of Antarctica is 2450 m;
therefore the Antarctic inland is an extremely cold
place and the air is rarefied. Confinement to Antarctica for certain periods and isolation from theoutside world produce various sources of stress(Palinkas, 1990). Such extreme environmental conditions cause hypoxia, mountain sickness, frostbite,depression and so on, but it is not easy to obtain dataon basic biochemical parameters.
Hypoxia stimulates vascular endothelial cells,
leukocytes and macrophages in vitro to release proinflammatory cytokines (Yan et al., 1995; Naldini
et al., 1997). Interleukin-6 (IL-6) is a mediator of
the inflammatory response and the production ofacute phase proteins (Bendtzen, 1991; Herrmann etal., 1994; Adamik et al., 1997). Although several
studies examined cytokines at high altitudes, theirstudies examined rapid changes in IL-6 in a shortperiod (Klausen et al., 1997; Hartmann et al., 2000).
We evaluated the influence of such conditions(high altitudes, hypoxia, cold, mental stress and soon) in the long term on health from the viewpoint ofcytokines in an Antarctic inland research party.

Subjects and Methods
The subjects were 7 members of an inland research
party participating in the 40th Japanese Antarctic
Research Expedition which lasted from 1998 toAbbreviations: CRP, C-reactive protein; EPO, erythropoietin; IL-6, interleukin-6; PaO2, arterial oxygen tension;
RBC, red blood cell29

S. Otani and H. Kusagawa

2000. All subjects were healthy Japanese men, andat the beginning of this study, their mean age was
33.7 ± 5.0 years (ranges 27 to 40). Although one ofthem (Subject X) broke his right 2nd, 3rd and 4th
metatarsal bones after the 1st blood sampling, thesefractures healed under conservative therapy, and hecould join this group. The subjects gave informed
consent, and the experimental protocol was approved by the Headquarters of Japanese Antarctic Research Expedition and National Institute of PolarResearch, Japan.
The subjects split up and set off in 4 largesnow vehicles measureing 3.5 × 7 m. The party left
Showa Station (69˚00'S, 39˚35'E, 29 m above sealevel), the Japanese Antarctic base, on November 1,1999, and took 4 weeks to Dome Fuji Station (77˚19'S, 39˚42'E, 3810 m), the Japanese Antarctic inland base. They began to survey after 2 weeks oftheir stay at Dome Fuji Station, and returned toShowa Station on February 11, 2000. In these areas
the sun does not set in December and January because of the high southern latitude. The following
was their daily work schedule. The subjects got up
at 0600, had a 3 regular balanced meals a day andwent to bed at 2200. They drove snow vehicles
about 50 km in 6 h and did outdoor work for shortperiods, 10 to 30 min, several times a day. Thenormal temperature inside the vehicles was about
20˚C, but only –10˚C in early morning since theirvehicles had not been warmed up yet.
Arterial blood was sampled indoors or within
the snow vehicles (20˚C) at the following points:
A, Showa Station 1 month before departure; B, at a3032-m altitude 15 days after the start of the expedition; C, Dome Fuji station on Day 34 (Day 1, thedeparture day); D, at 2960 m on Day 53; E, at 2077
m on Day 65; F, Showa Station 5 days after theirreturn. The atmospheric pressure and outside temperature at each blood sampling point are shown inTable 1.
We measured the levels of Hb, red blood cell(RBC) count and serum erythropoietin (EPO) as theindexes of hematological adaptation to hypoxia.
Serum levels of C-reactive protein (CRP) and IL-6
were measured as the indexes of inflammation andstress, respectively. We measured arterial oxygentension (PaO2), Hb and RBC count by a portableclinical analyzer, i-STAT (i-STAT Co., East Windsor,
NJ), and a microscope, as soon as the blood wassampled. Serum samples were then immediately
frozen at –20˚C and stored at –80˚C after the expedition until analysis. The serum CRP level wasmeasured by latex agglutination immunoassay,
serum EPO level by radioimmunoassay and serumIL-6 level by chemiluminescent enzyme immunoassay. By use of a modified van Beaumont formula(Dill and Costill, 1975), calculations were made of
the % change in plasma volume from the initialpoint to each point.
Moreover, the occurrence of mountain sickness during the expedition was investigated. Symptoms of mountain sickness observed were headache, gastrointestinal symptoms (anorexia, nausea
or vomiting), fatigue or weakness, dizziness or lightheadedness and difficulty in sleeping, which werequantified on the basis of the Lake Louise consensus on the definition of altitude illness (Roach et al.,1993). In counting the severity of each symptom, 1point was given for mild involvement, 2 points formoderate, 3 points for severe and 4 points for extreme involvement. The mountain sickness score
was taken as the sum of the points.
Intergroup differences were examined byanalysis of variance. Relationships among variables were ascertained by Spearman’s correlation
coefficient by the rank sum test. Differences wereconsidered statistically significant at P < 0.05.

Results
The PaO2 decreased significantly as the atmospheric pressure gradually decreased, showing a positive
correlation (r = 0.92, P < 0.001). At the start of theexpedition, the serum concentration of EPO increased significantly (48.1 ± 25.0 mU/mL, normal
level 8 to 36 mU/mL), while the RBC count increased later, after the peak of EPO. The Hb levels
peaked at Point E, after the peak of the RBC count.
There was no significant change in serum CRP during this period (Table 1).

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Changes in cytokines in Antarctica

Table 1. Climate and clinical parameters at different determination points

Time after departure (day)Altitude above sea level (m)Atmospheric pressure (hPa)
Air temperature(˚C)
PaO2(mmHg)

Blood-sampling point
CDA

B

–29
974.9
–14.6

15
3,032
657.9
–34.2

86.1 ±13.749.9 ± 3.8(mU/mL)

20.3 ± 7.7

53
2,960
666.1
–25.3

65
2,077
732.7
–19.2

108
29
982.5
–2.3

44.3 ± 5.3

57.3 ± 5.1

62.6 ± 2.6

93.3 ± 8.0

**

**
** **

38.5 ±23.1

48.1±25.0

**

**

RBC

(× 10 /µL)

463 ± 52484 ± 66**
Hb(mg/dL)

14.5 ± 1.6567 ± 75**15.6 ± 0.5**
CRP(mg/dL)

Mountain sickness score**
16.9 ± 0.9**

0.1 ± 0.1

0.1 ± 0.2

—1.6 ± 1.3**

16.5 ± 4.5

** **
**

551 ± 65

14.5 ± 6.5**

513 ± 48****497 ± 51** ***17.9 ± 1.5

* **
**

**
**

**
** **

16.2 ± 5.3*
4F

343,810585.1
–41.7

*
** **
EPO

E

18.0 ± 1.0

** **
** **

16.3 ± 1.2****

0.0 ± 0.0

0.0 ± 0.0

0.0 ± 0.0

0.0 ± 0.0

0.7 ± 0.8

0.1 ± 0.40.0 ± 0.0—****

Number of subjects, 7.
All results are shown as mean ± SD.
A–F, see the text.
CRP, C-reactive protein; EPO, erythropoietin; PaO2, arterial oxygen tension; RBC, red blood cell.
* P < 0.05.
** P < 0.01.

The time changes in serum concentration ofIL-6 are illustrated in Table 2. Except for Subject
X, serum concentrations of IL-6 were within normal ranges (< 4.0 pg/mL) 1 month before departure(Point A). The levels then rose significantly higher
than the initial Point-A level (0.58 ± 0.15 pg/mL) at
Point B (1.28 ± 0.45 pg/mL, P < 0.05), and returned
to nearly the initial level at Point F (0.57 ± 0.27 pg/mL). The highest serum IL-6 level was found at
Point E (1.38 ± 0.89 pg/mL), which was significantly higher than at Points A and F (P < 0.05 and P <0.01). The plasma volumes decreased by anaverage of 9%, 22%, 32%, 34% and 19% at Points
B, C, D, E and F, respectively. Thereby the meanserum IL-6 at each point was overestimated by 9%,28%, 43%, 48% and 21%, respectively. However,31

S. Otani and H. Kusagawa

Table 2. Changes in the serum concentration of IL-6

IL-6(pg/mL)

AB

0.58 ± 0.15

1.28 ± 0.45

Blood-sampling pointCD
1.03 ± 0.54*
Corrected IL-6† (pg/mL)

0.58 ± 0.15

0.95 ± 0.45

0.81 ± 0.47

0.67 ± 0.33

*

*

F

1.38 ± 0.89**
1.18 ± 0.50

E*

0.57 ± 0.27**

0.94 ± 0.65

0.47 ± 0.23***

Number of subjects, 6, excepting for one who suffered the bone fractures.
All results are shown as mean ± SD.
† The level of IL-6 after correction for hemoconcentration.
A–F, see the text.
IL-6, interleukin-6.
* P < 0.05.
** P < 0.01.

even with corrections for hemoconcentration, theIL-6 level at Point B would be higher than those at
Points A, D and F (P < 0.05, P < 0.05 and P < 0.01,respectively). The value of IL-6 at Point E would
still be higher than at Point F (P < 0.05). Subject X
had a very high concentration of IL-6 at every
determination point; the values at Points A to F
were 36.2, 103.0, 56.8, 44.6, 45.4 and 36.7 pg/mL,respectively.
Mild mountain sickness was observed in 5 of
the men 2 weeks after departure. Although 4 ofthem showed symptoms of exposure to cold, suchas headache, nasal congestion and fatigue, they recovered within 2 to 10 days. However, Subject X
showed unusual headache and general fatigue persisted for 6 weeks.
The concentration of IL-6 did not correlatewith the PaO2 (r = –0.28, P = 0.07), EPO level (r =0.04, P = 0.79) and mountain sickness score (r =0.28, P = 0.08).

serum concentration of EPO promptly increased:
this reaction, we thought, was necessary for humans
to adapt to a high altitude. Since the number oferythrocytes peaked within 6 weeks, one may conclude that hematological adaptation to a high altitude is completed in several weeks (Wilkerson,1975).
The concentrations of IL-6 at Points B and E
were higher than those at a low altitude. It is known
that hypoxia increases serum IL-6 (Klausen et al.,
1997; Hartmann et al., 2000). Klausen et al. (1997)
reported that the values of serum IL-6 were related
to arterial blood oxygen saturation and EPO values,
with rapidly reacting changes in a short period. We
could not examine early changes in cytokines because of other various inland research and a strict
work schedule. In our long-term observation, theserum concentration of IL-6 was not related toserum EPO and hypoxemia. Since the concentration of IL-6 did not correlate with the PaO2 in thisstudy, factors other than low oxygen may also contribute to this change. Changes in serum CRP werevery slight, and therefore, inflammation might haveno association with changes in IL-6.
Cold itself was determined to have had little
influence on results because the subjects spent mostof their time within the snow vehicles, which wereheated. We thought that cold in this study was aDiscussion
Cold, low pressure and low oxygen are known toaffect human physiology at high altitudes. Amongthese factors, low oxygen is considered to be themost important. In this study, we observed that the32Changes in cytokines in Antarctica

temporary stimulus, and one of psycholgical stressors. Several studies examined that psychologicalstress is associated with an increase in serum concentration of IL-6 (Maes et al., 1999; Song et al.,1999). It has been reported that the restrain stressincreased the plasma concentrations of IL-6 in mice
(Nukina et al., 1988). Lantis (1968) observed thatthe social environment of polar regions would comprise a more potent source of stress than the physical environment. In our study, the serum concentration of IL-6 increased again after hematological
adaptation to the altitude was assumed to be completed. Although we could not estimate the mental
conditions of the subjects objectively, psychological stress under such conditions may also have contributed to the increase of IL-6.
The changes in IL-6 were slight in general; in
Subject X, however, IL-6 remarkably increased
during the trip. The fractures he suffered before
departure and a kind of posttraumatic stress disorder (Maes et al., 1999) in addition to hypoxia
were thought to be the reasons for this change. On
the other hand, since his symptoms of mountainsickness were severer than in the others, elevationof IL-6 may be related to mountain sickness.
We were unable to identify any backgroundfactor that might explain why the serum concentration of IL-6 changed in this research. However,none of the subjects suffered from severe mountainsickness like pulmonary and brain edema becauseof the slow rise in altitude. All subjects remained inrelatively good health for 3 months: the humanbody is proof that humans can survive in extreme
environmental conditions in Antarctica and acclimating to such surroundings is possible.

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Received April 11, 2003; accepted May 21, 2003
Corresponding author: Shinji Otani, MD, PhD

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