activity [51]. Additionally, NF-κB nuclear translocation and binding to the IL-10
promotor increase, resulting in an enhanced expression of the anti-inflammatory
cytokine IL-10.
The role described for HDAC3 in the NF-κB pathway in macrophages is an
example, highlighting the potential for HDAC3-selective inhibition. Nevertheless, it
should be noted that HDACs potentially target thousands of substrates, including
many other transcription factors and general transcriptional regulators. However, it is
to be expected that only a few potential lysine acetylation and deacetylation events
have functional consequences. Therefore, it is important to identify these crucial
events and the enzymes involved. This provides chances to find specific effects in
specific disease models. Taken together, the current evidence indicates that HDAC3
is an important player in pro- and anti-inflammatory gene transcription and that
HDAC inhibitors with isoenzyme selectivity among HDAC1, HDAC2, and HDAC3
have potential as anti-inflammatory agents.
2.6 Deacetylase and Acetyltransferase Expression in Asthma
Asthma is a heterogeneous disease with many different clinically overlapping subtypes. Prototypically, asthma is considered to be an allergic disorder mediated by
mast cells, eosinophils, and T-helper cells (CD4
+
) [58]. The importance of IL-8 in
COPD is mirrored by IL-5 in asthma, which induces eosinophil generation in the
bone marrow and leads to a subsequent increase in eosinophils in the lung [59]. Additionally, IL-4 is a key cytokine that enhances IgE-mediated immune responses in
allergic airway inflammation [60]. Asthma is further clinically characterized
by increased sensitivity of the airways to an inhaled constrictor agonist, like
methacholine, termed airway hyperresponsiveness [61]. Looking at the balance
between acetylases and deacetylases in patients with mild, stable asthma, a much
more complicated balance is found compared to COPD. One study showed that
histones were acetylated to a significantly higher extent in bronchial biopsies of
asthma patients compared to healthy individuals and that this may be caused by a
small but significant decrease in the expression of both HDAC1 and HDAC2
[62]. The expression of other HDACs was not evaluated, but it was shown that
HDAC1 to HDAC6 were present primarily within the epithelium and to a lesser
extent in infiltrating inflammatory cells. Another study analyzed the deacetylase
activity in alveolar macrophages from asthmatic patients and found a decrease,
related to a decrease in the expression of HDAC1, but not HDAC2 nor HDAC3
[63]. In circulating blood monocytes, no differences in HDAC activity were found,
further confirming that differences in HDAC expression only occur locally at or near
the site of inflammation. Taken together these results show that the expression levels
of HDAC1, HDAC2, and HDAC3 are affected to a much lesser extent in asthma
compared to COPD. This may have important consequences for treating this disease
with HDACi. Unfortunately, neither the expression and activity of other HDACs nor
the role of acetyltransferases has been adequately characterized in asthma.
438
M. R. H. Zwinderman et al.
promotor increase, resulting in an enhanced expression of the anti-inflammatory
cytokine IL-10.
The role described for HDAC3 in the NF-κB pathway in macrophages is an
example, highlighting the potential for HDAC3-selective inhibition. Nevertheless, it
should be noted that HDACs potentially target thousands of substrates, including
many other transcription factors and general transcriptional regulators. However, it is
to be expected that only a few potential lysine acetylation and deacetylation events
have functional consequences. Therefore, it is important to identify these crucial
events and the enzymes involved. This provides chances to find specific effects in
specific disease models. Taken together, the current evidence indicates that HDAC3
is an important player in pro- and anti-inflammatory gene transcription and that
HDAC inhibitors with isoenzyme selectivity among HDAC1, HDAC2, and HDAC3
have potential as anti-inflammatory agents.
2.6 Deacetylase and Acetyltransferase Expression in Asthma
Asthma is a heterogeneous disease with many different clinically overlapping subtypes. Prototypically, asthma is considered to be an allergic disorder mediated by
mast cells, eosinophils, and T-helper cells (CD4
+
) [58]. The importance of IL-8 in
COPD is mirrored by IL-5 in asthma, which induces eosinophil generation in the
bone marrow and leads to a subsequent increase in eosinophils in the lung [59]. Additionally, IL-4 is a key cytokine that enhances IgE-mediated immune responses in
allergic airway inflammation [60]. Asthma is further clinically characterized
by increased sensitivity of the airways to an inhaled constrictor agonist, like
methacholine, termed airway hyperresponsiveness [61]. Looking at the balance
between acetylases and deacetylases in patients with mild, stable asthma, a much
more complicated balance is found compared to COPD. One study showed that
histones were acetylated to a significantly higher extent in bronchial biopsies of
asthma patients compared to healthy individuals and that this may be caused by a
small but significant decrease in the expression of both HDAC1 and HDAC2
[62]. The expression of other HDACs was not evaluated, but it was shown that
HDAC1 to HDAC6 were present primarily within the epithelium and to a lesser
extent in infiltrating inflammatory cells. Another study analyzed the deacetylase
activity in alveolar macrophages from asthmatic patients and found a decrease,
related to a decrease in the expression of HDAC1, but not HDAC2 nor HDAC3
[63]. In circulating blood monocytes, no differences in HDAC activity were found,
further confirming that differences in HDAC expression only occur locally at or near
the site of inflammation. Taken together these results show that the expression levels
of HDAC1, HDAC2, and HDAC3 are affected to a much lesser extent in asthma
compared to COPD. This may have important consequences for treating this disease
with HDACi. Unfortunately, neither the expression and activity of other HDACs nor
the role of acetyltransferases has been adequately characterized in asthma.
438
M. R. H. Zwinderman et al.