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The following is the abstract of the article discussed in the subsequent letter.
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ABSTRACT |
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Rhind, Shawn G., John W. Castellani, Ingrid K. M. Brenner, Roy
J. Shephard, Jiri Zamecnik, Scott J. Montain, Andrew J. Young, and Pang
N. Shek. Intracellular monocyte and serum cytokine expression is modulated by
exhausting exercise and cold exposure. Am J Physiol
Regulatory Integrative Comp Physiol 281: R66-R75, 2001.
This
study tested the hypothesis that exercise elicits monocytic cytokine
expression and that prolonged cold exposure modulates such responses.
Nine men (age, 24.6 ± 3.8 yr; 
O2 peak, 56.8 ± 5.6 ml · kg
1 · min1) completed
7 days of exhausting exercise (aerobic, anaerobic, resistive) and
underwent three cold, wet exposures (CW). CW trials comprised 
6 h
(six 1-h rest-work cycles) exposure to cold (5°C, 20 km/h wind) and
wet (5 cm/h rain) conditions. Blood samples for the determination of
intracellular and serum cytokine levels and circulating hormone
concentrations were drawn at rest (0700), after exercise (~1130), and
after CW (~2000). Whole blood was incubated with (stimulated) or
without (spontaneous) lipopolysaccharide (LPS; 1 µg/ml) and stained
for CD14 monocyte surface antigens. Cell suspensions were stained for
intracellular cytokine expression and analyzed by flow cytometry. The
proportion of CD14+ monocytes exhibiting spontaneous and
stimulated intracellular expression of interleukin (IL)-1
, IL-6, and
tumor necrosis factor (TNF)-
increased after exercise, but these
cells produced less IL-1 and TNF- after CW when CW was preceded
by exhausting exercise. Serum cytokine concentrations followed a
parallel trend. These findings suggest that blood monocytes contribute
to exercise-induced cytokinemia and that cold exposure can
differentially modulate cytokine production, upregulating expression of
IL-6 and IL-1 receptor antagonist but downregulating IL-1 and
TNF-. The cold-induced changes in cytokine expression appear to be
linked to enhanced catecholamine secretion associated with cold exposure.
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LETTER |
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To the Editor: In a very important study, Rhind et
al. (4) recently reported that 1) intracellular
monocyte cytokine production contributes to the exercise-induced
cytokinemia, 2) the increase in cytokine production in
monocytes corresponds with the increase in plasma cytokine
concentration, and 3) the effects are likely mediated by
alterations in the sympathoadrenal response. In reporting these
results, Rhind et al. (4) have not compared their results with anomalous previously published work. In contrast with the data by
Rhind et al. (4), convincing evidence demonstrates that
monocytes do not contribute to the exercise-induced increase in plasma
levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-. In a
recent study (5), published before the submission by Rhind
et al. (4), human subjects exercised for 120 min on a
cycle ergometer at 70% of peak oxygen uptake
(O2 peak) on two occasions with or
without the ingestion of carbohydrate. Starkie et al. (5)
observed that neither the number nor the percentage of
monocytes producing IL-6 or TNF- increased as a result of an acute
exercise bout. Importantly, the amount of spontaneously produced
cytokine in each monocyte was either unchanged or decreased after
exercise (5). This demonstrated that the circulating monocytes could not have been the source of the exercise-induced cytokinemia. Moreover, carbohydrate ingestion, which blunted the epinephrine response, did not affect monocyte intracellular cytokine production. It was concluded, therefore, that circulating monocytes are
not the source of the exercise-induced increase in plasma IL-6 and that
attenuating the sympathoadrenal response has no effect on monocyte
cytokine production. In this study (5), the increase in
plasma IL-6 was subtle, and in a subsequent study (7),
blood was sampled from highly performed marathon runners before
and after a marathon run. Despite an increase in plasma IL-6 from 2 pg/ml at rest to 120 pg/ml after the marathon, the number of monocytes
spontaneously producing IL-6 and the mean fluorescence intensity of the
cells producing IL-6 actually decreased as a result of exercise. It was
again concluded that monocytes do not contribute to the
exercise-induced increase in IL-6 or, for that matter, TNF-. Of
note, the absence of any increase in monocyte intracellular cytokine
production was observed in the face of large increases in epinephrine
and norepinephrine, again suggesting that the catecholamines do not
increase cytokine production by leukocytes. To confirm that adrenergic
stimulation does not mediate leukocyte cytokine production, it was
recently demonstrated that combined - and -adrenergic blockade
does not affect the exercise-induced suppression of lymphocyte cytokine
production (8). These previous studies (5, 7,
8) are not anomalous with existing literature. Indeed, Rhind et
al. (4) concede that previous studies (one from their own
laboratory) have not observed increases in cytokine gene expression in
monocytes after prolonged exercise (2, 11). In addition,
it has been demonstrated that IL-6 gene expression is not only observed
in resting skeletal muscle but that gene expression increases
severalfold in response to acute exercise (3, 6). In
addition, in a recent study, which utilized the arteriovenous balance
technique, Steensberg et al. (9) demonstrated that the
exercise-induced increase in IL-6 could be accounted for solely by the
release from contracting skeletal muscle during prolonged single-legged
kicking. Taken together, the existing literature demonstrates that
monocyte intracellular cytokine production does not increase in
response to acute exercise and that contracting skeletal muscle is a
more likely candidate.
Why then do the data of Rhind et al. (4) contradict the
evidence that suggests that monocytes do not contribute to the increase in plasma cytokines after acute exercise? The methodology appears robust; in fact, it is remarkably similar to the methodology extensively reported in a previous study (5). However,
there are subtle differences in the analyses of the data that require consideration. Rhind et al. (4) report their intracellular data as percentage of CD14+ cells producing each individual
cytokine. Although reporting percentages provides useful information,
it does not allow for sufficient analyses to make definitive
conclusions. In Table 1 of their study, Rhind et al. (4)
provide data to show that circulating monocytes increased by ~10%
when comparing post- with preexercise. They then report that the
percentage of monocytes expressing individual cytokines increased.
However, by neglecting to report the fluorescence intensity, i.e., how
much cytokine the cell is producing, one cannot truly ascertain whether
the cytokine production by monocytes actually contributes to the
exercise-induced increase in plasma cytokine concentration. To fully
interpret monocyte intracellular cytokine production, the percentage of monocytes producing each cytokine must be reported in conjunction with
the number of monocytes producing cytokine and the fluorescence intensity. In addition, the choice of surface marker, CD14+
in the case of Rhind et al. (4), is crucial because of
mitogen binding. CD14+ may not be the ideal cell surface
marker antibody, particularly when analyzing lipopolysaccharide
(LPS)-stimulated blood, because LPS has been found to bind to
CD14+ and increase its cell surface expression
(1). It would appear, therefore, that CD33+ is
a more appropriate cell surface staining antibody to utilize. Notwithstanding any methodological flaws associated with the data of
Rhind et al. (4), it is plausible that the data represent an accurate indication of the immunological response to exercise. In
fact, we believe that their data are complementary to those published
previously. However, it is surprising to us that the authors would
suggest that the findings "demonstrate that blood monocytes are a
source of IL-1, IL-1 receptor antagonist (IL-1ra), IL-6, and TNF-
production after acute, strenuous exercise" when they appear not to
have examined the effect of acute, strenuous exercise on monocyte
cytokine production. Despite the fact that the authors state that blood
samples were obtained "at rest (0700), 30 min after fatiguing
exercise (~1130), and 30 min after cold wet exposure (~2000) on
days 1 and 8," this appears not to be the case.
Figures 1-3 of their study all indicate that exercise was not
performed on day 1. Therefore, it is quite plausible that the combination of 8 days of exercise and cold, wet exposure would lead
to cytokine production in immunocompetent cells. However, to suggest
that the results indicate that monocytes are a source of plasma
cytokine concentration after "acute" exercise appears misleading.
Furthermore, the assertion that monocyte cytokine production is
mediated by the sympathoadrenal response is based on a temporal
relationship and not supported by studies where the catecholamines have
been perturbed by an experimental intervention.
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REFERENCES |
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1.
Kitchens, RL,
Thompson PA,
O'Keefe GE,
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Munford RS.
Plasma constituents regulate LPS binding to, and release from, the monocyte cell surface.
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4.
Rhind, SG,
Castellani JW,
Brenner IKM,
Shepherd RJ,
Zamecnik J,
Montain SJ,
Young AJ,
and
Shek PN.
Intracellular monocyte and serum cytokine expression is modulated by exhausting exercise and cold exposure.
Am J Physiol Regulatory Integrative Comp Physiol
281:
R66-R75,
2001
5.
Starkie, RL,
Angus DJ,
Rolland J,
Hargreaves M,
and
Febbraio MA.
Effect of prolonged, submaximal exercise and carbohydrate ingestion on monocyte intracellular cytokine production in humans.
J Physiol (Lond)
528:
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6.
Starkie, RL,
Arkinstall MJ,
Koukoulas I,
Hawley JA,
and
Febbraio MA.
Carbohydrate attenuates the increase in plasma IL-6, but not in skeletal muscle IL-6 mRNA, during exercise in humans.
J Physiol (Lond)
533:
585-591,
2001
7.
Starkie, RL,
Rolland J,
Angus DJ,
Anderson MJ,
and
Febbraio MA.
Circulating monocytes are not the source of elevations in plasma IL-6 and TNF- levels after prolonged running.
Am J Physiol Cell Physiol
280:
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8.
Starkie, RL,
Rolland J,
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Effect of adrenergic blockade on lymphocyte cytokine production at rest and during exercise.
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281:
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9.
Steensberg, A,
van Hall G,
Osada T,
Sachetti M,
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Local production of IL-6 in contracting skeletal muscles can account solely for the exercise-induced increase in plasma IL-6.
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Mark A. Febbraio, Copenhagen Muscle Research Centre Rigshospitalet, Section 7652 DK-2200 Copenhagen N, Denmark E-mail: m.febbraio{at}physiology.unimelb.edu.au | ||||||||||||
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Rebecca L. Starkie, Department of Physiology The University of Melbourne Parkville, Victoria 3010, Australia |
To the Editor: We appreciate the opportunity to
respond to the letter by Febbraio and Starkie with respect to our
publication in the American Journal of Physiology: Regulatory,
Integrative and Comparative Physiology (9) concerning the
unresolved issue of the cellular origin of cytokines during exercise.
Febbraio and Starkie contend that blood "monocytes are not the
source" of the exercise-induced cytokinemia, suggesting
instead that "contracting skeletal muscle is a more likely
candidate" for peripheral cytokine release. We agree with their
assertion that methodological differences between our studies could
account for the disparate findings concerning intracellular (IC)
monocytic cytokine production; however, in light of evidence presented
in this rebuttal, we submit that the data of Febbraio and colleagues do
not prove categorically that monocytes cannot be a source of
cytokines with acute exercise.
Although we concur that the choice of cell surface markers is crucial
to the validity of results obtained when assessing IC cytokine
expression, we dispute the view that the pan-myeloid marker CD33 is
"more appropriate" than CD14 as a cell surface marker for blood
monocytes. In fact, increased sophistication in multiparameter cell
phenotype analysis by flow cytometry demonstrates that monocytes are an
extremely heterogeneous cell population (comprising at least 5 subsets)
with respect to their expression of an array of surface markers and
their functional characteristics, including the pattern of cytokines
they produce (1). Recognizing this heterogeneity, we consider the use
of any single "lineage-specific" surface marker to be less than
ideal for the identification of blood monocytes.
Consequently, we routinely employ a multicolor staining protocol, which
has been adopted for the consensus definition of human blood monocytes
(18). This approach relies on coexpression of CD14, CD16, CD33, and
HLA-DR surface antigens and provides a clear distinction of
phenotypically and functionally discrete monocyte subpopulations (1).
This includes the identification of two main monocyte subsets, on the
basis of their cytokine production profiles: a
CD14brightCD16dim/
REPLY
CD33bright
subset, which expresses low levels of cytokines, and a
CD14dimCD16brightCD33dim
subset, which expresses high levels of inflammatory cytokines (Fig.
1, A and B,
respectively). The latter subset has been likened to a "circulating
macrophage" (12, 19) and is known to be rapidly and selectively
mobilized from the marginal pool (via -adrenergic mechanisms) with
exercise (3, 7, 16). Also, using this staining combination allows for
the exclusion of CD33bright,
CD14CD16, and HDL-DR+
peripheral blood dendritic cells; this is notable because
dendritic cells exhibit a unique pattern of cytokine production (1, 2) and also increase appreciably with exercise (4, 17).
View larger version (33K):
[in a new window]
Fig. 1.
Differential cytokine production
profiles by CD14brightCD16dim/
(A) and CD14dimCD16bright
(B) monocyte subsets.
CD14dimCD16bright cells exhibit
higher inflammatory cytokine production and appear to be the primary
subset of blood monocytes responsible for enhanced spontaneous cytokine
production with exercise. TNF-, tumor necrosis factor-; IL,
interleukin.
Although we were unable to exploit this multicolor staining approach in
our collaborative field study with the U.S. Army (9), we have used it
extensively to identify a panel of IC cytokines in critically ill
patients (10, 11) and subsequently to characterize IC cytokine
expression with acute exercise. This approach has reliably demonstrated
a differential pattern of spontaneous cytokine expression (IL-1 > TNF- > IL-6) with respect to the proportion, number, and mean
fluorescence intensity (MFI) of cytokine-producing monocytes in
response to strenuous exercise. Moreover, our findings reveal that this
differential monocytic cytokine expression can be traced to differences
in the relative cytokine expression by regular
CD14brightCD16dim/ vs.
CD14dimCD16bright monocyte subsets in response
to exercise (Fig. 2). While IC cytokine expression may not change significantly with acute exercise when gating
on total CD14 monocytes, a more detailed subset examination demonstrates significant increases in the expression (percentage and
MFI) of IC cytokines by CD14dimCD16bright
monocytes. For example, in the case of IL-6, a postexercise doubling of
MFI by CD14dimCD16bright cells is offset by
concomitant reductions in the
CD14brightCD16dim/ subset. At the same time,
CD14dimCD16bright cell numbers increase
dramatically (3- to 4-fold) with exercise (7, 16); hence it follows
that net peripheral cytokine production by this subset would be
enhanced after exercise.
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Given this, we feel that measures of total monocytic cytokine expression, in the absence of specific subset analysis, are inadequate and may lead to the erroneous conclusion that monocytic cytokine production is unaffected by exercise. Likewise, we believe that the use of CD33 (in conjunction with side scatter) as the sole marker for the putative identification of blood monocytes is inappropriate and misleading because it does not adequately allow for the distinction of these important functional subsets and may in fact lead to confounding results due to the inclusion of peripheral blood dendritic cells.
Furthermore, we dismiss the idea that LPS stimulation can cause an
artifactual increase in CD14 surface marker expression. This notion is
simply not supported by the literature or by our own findings. On the
contrary, there is overwhelming evidence that long-term LPS stimulation
(
24 h) leads to CD14 receptor shedding and downregulation of CD14
surface density. We have extensively evaluated the kinetics of CD14
receptor expression using multiple incubation times, and in our hands,
LPS stimulation does not significantly reduce either the percentage of
CD14+ cells or their MFI, over relatively short (3-4
h) incubation periods. Indeed, the bulk of the published literature on
monocytic IC cytokine staining supports the use of anti-CD14 as the
single marker of choice (1, 6, 13).
Another important methodological issue that deserves mention is related to the addition of the cytokine secretion inhibitor brefeldin A (BFA) to unstimulated whole blood for the analysis of spontaneous IC cytokine production. We have learned from experience with clinical specimens that when measuring spontaneous monocytic cytokine expression, it is critical to prespike heparinized vacutainers with BFA before blood draw. This ensures a more accurate snapshot of in vivo cytokine expression at the time of sampling by preventing the loss of cytokines from the producing cells during specimen handling. In fact, we have observed as much as a 10% increase in the proportion of cytokine-positive monocytes using this approach, compared with postsampling addition of BFA. Obviously, this is very important when trying to accurately quantify the relatively small changes in cytokine production with exercise and could be especially significant in field trials, where longer sample processing times are common, such as the design involving marathon runners described by Starkie et al. (15).
Recent studies present a compelling argument that active skeletal muscle is a significant source of IL-6 (and possibly other cytokines) with exercise (5, 8); however, theses studies do not preclude the contribution of peripheral immune cells to circulating cytokinemia. In fact, the issue of which cell types within muscle are responsible for enhanced cytokine production is unresolved. Myoblasts are known to synthesize various cytokines, but it remains plausible that resident or infiltrating cells (including cells of the monocytic lineage) contribute to intramuscular cytokine production. Moreover, recent data from Starkie et al. (14) identify a discordance between changes in intramuscular IL-6 mRNA levels and plasma IL-6 concentration after exercise, leading them to conclude that muscle cannot "solely account for exercise-induced increases in plasma IL-6" and that "IL-6 production by tissues other than skeletal muscle" must exist. Nevertheless, the authors discount the possibility that blood monocytes might contribute to IL-6 production on the basis of their previous findings (15), which used CD33 alone to quantify monocytic IL-6. We would strongly suggest that this conclusion warrants reevaluation and further postulate that circulating CD14+CD16+ monocytes could well contribute to the shortfall in IL-6 production.
Collectively, the data presented here clearly demonstrate that specific subsets of blood monocytes (i.e., CD14+CD16+ cells) can be a source of cytokine production in association with acute exercise and that it is no longer sufficient to define monocytes on the basis of a single marker. A more appropriate approach for the identification of blood monocytes and their distinct functional attributes (i.e., cytokine production) requires the use of multiple cell surface markers. We propose that future exercise immunology studies should follow a more standardized method for the identification of monocytes to better characterize the functional role of these important exercise-responsive cells. In short, reports of the demise of the monocyte with exercise seem greatly exaggerated.
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FOOTNOTES |
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10.1152/ajpregu.00702.2001
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|
Shawn G. Rhind, Biomedical Sciences Section Defence & Civil Institute of Environmental Medicine Toronto, Ontario M3M 3B9, Canada E-mail: shawn.rhind{at}dciem.dnd.ca | ||||||||||||
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Pang N. Shek, Biomedical Sciences Section Defence & Civil Institute of Environmental Medicine Toronto, Ontario M3M 3B9, Canada |
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