Mechanisms for the anti-inflammatory effects of statins.

Abstract

Statins have diverse effects on the cellular mediators of inflammation and immunity that may be partially responsible for their efficacy in preventing cardiovascular disease, and which have encouraged their use in treating immune/inflammatory diseases. We discuss a selection of recently published studies that provide new insights into the mechanisms by which statins exert anti-inflammatory effects.
Statins have a variety of direct effects on the gene expression and function of cells of both the innate and adaptive immune systems, including endothelial cells, macrophages, dendritic cells and T cells. Many of these effects are related to statin blockade of GTPase isoprenylation, as has been shown in older literature, although newly identified cell type-specific downstream pathways of GTPase have been described. Recently published analyses of data from clinical trials have also provided further evidence that statin therapy has anti-inflammatory effects and benefits independent of lowering cholesterol.
Ongoing research continues to strengthen the case that statins can modulate immune responses by several mechanisms, independent of lowering blood cholesterol. A major challenge for investigators will be to determine how to take advantage of these new mechanistic insights to improve treatment of cardiovascular disease and primary immune/inflammatory disorders.

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Mechanisms for the anti-inflammatory effects of statins
De-xiu Bu, Gabriel Griffin and Andrew H. Lichtman
Introduction
3-Hydroxy-3-methylglutaryl(HMG)-CoAreductaseisthe
key rate-limiting enzyme of the mevalonate pathway for
both cholesterol biosynthesis and for generation of iso-
prenoidsrequiredforactivationofsmallGTPasesignaling
molecules. Statins inhibit this enzyme, which blocks
cholesterol synthesis and lowers blood LDL-cholesterol
levels. Several large clinical trials have provided ample
evidence supporting the use of statins in dyslipidemia for
primary and secondary prevention of cardiovascular dis-
ease. Nonetheless, there is a widely adopted view that
statins exert pleiotropic effects independent of lowering
cholesterol, and a significant proportion of these effects
may be considered to be anti-inflammatory [1–4].
In this review, we will discuss a selection of recently
published articles that provide new insights into mech-
anisms by which statins may exert anti-inflammatory
effects on isolated cells in vitro and in vivo. We have
organized the discussion to emphasize the effects of
statins on components of the innate/inflammatory
response and adaptive immunity. We will also discuss
some recent clinical studies that address the putative
anti-inflammatory effects of these drugs in patients.
Effects of statins on innate immune
responses
Endothelial activation, which triggers venular leukocyte
adhesion and transmigration and movement of plasma
proteins out of capillaries, is a fundamental aspect of
innate immune responses to tissue injury and infection.
Multiple lines of investigation have previously estab-
lished that statins downmodulate the proinflammatory
andprothromboticfunctionsofendothelialcells.Arecent
review on the effects of statins on endothelial cells [5?]
highlights mechanisms by which statins induce endo-
thelial nitric oxide synthase (eNOS) expression, namely
through inhibition of Rho/ROCK signaling, activation of
PI3K/Akt and suppression of caveolin-1. Other previous
studies have shown that statins affect endothelial cells
through the induction of the transcription factor Kruppel-
like factor 2 (KLF2) and its target genes [6]. A study by
Lin et al. [7?] further characterized KLF2-dependent
effects of statins in endothelial cells. They found that
Department of Pathology, Brigham and Women’s
Hospital, Harvard Medical School, Boston,
Massachusetts, USA
Correspondence to Andrew H. Lichtman, MD, PhD,
Brigham and Women’s Hospital, NRB Room 752N,
77 Avenue Louis Pasteur Boston, MA 02115, USA
Tel: +1 617 525 4335; fax: +1 617 525 4333;
e-mail: alichtman@rics.bwh.harvard.edu
Current Opinion in Lipidology 2011, 22:165–170
Purpose of review
Statins have diverse effects on the cellular mediators of inflammation and immunity that
may be partially responsible for their efficacy in preventing cardiovascular disease, and
which have encouraged their use in treating immune/inflammatory diseases. We
discuss a selection of recently published studies that provide new insights into the
mechanisms by which statins exert anti-inflammatory effects.
Recent findings
Statins have a variety of direct effects on the gene expression and function of cells of
both the innate and adaptive immune systems, including endothelial cells,
macrophages, dendritic cells and T cells. Many of these effects are related to statin
blockade of GTPase isoprenylation, as has been shown in older literature, although
newly identified cell type-specific downstream pathways of GTPase have been
described. Recently published analyses of data from clinical trials have also provided
further evidence that statin therapy has anti-inflammatory effects and benefits
independent of lowering cholesterol.
Summary
Ongoing research continues to strengthen the case that statins can modulate immune
responses by several mechanisms, independent of lowering blood cholesterol. A major
challenge for investigators will be to determine how to take advantage of these new
mechanistic insights to improve treatment of cardiovascular disease and primary
immune/inflammatory disorders.
Keywords
inflammation, innate immunity, statins, T cells
Curr Opin Lipidol 22:165–170
? 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
0957-9672
0957-9672 ? 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/MOL.0b013e3283453e41

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CCN3, a member of the CCN (Cyr61, Ctgf and Nov)
family of cell growth regulators, is transcriptionally
regulated by KLF2, and inhibits the expression of vas-
cularcelladhesionmolecule-1andmonocyteadhesionby
human umbilical vein endothelial cells.
KLF4, another member of the Kruppel-like family, has
also been previously identified as a key regulator of
endothelialhomeostasis[8].ArecentstudybyOhnesorge
et al. [9?] has implicated KLF4 in mediating anti-inflam-
matory effects of statins on endothelial cells. The authors
showed that statins upregulate extracellular signal-
regulated kinase (Erk5) via the MEK5/mitogen activated
protein kinase pathway, and that many of the vasopro-
tective effects of Erk5 are dependent on KLF4 expres-
sion. In a related study, Villarreal et al. [10?] also showed
that KLF4 is upregulated in cultured human endothelial
cells by atheroprotective shear stress, statins and resver-
atrol. The effect of resveratrol on KLF4 was mediated by
a MEK5/myocyte enhancer factor 2 -dependent but
ERK5-independent pathway, although the role of this
pathway in mediating the statin effect on KLF4 was not
explicitly addressed. Interestingly, about 60% of the
genes regulated by the overexpression of activated
MEK5 were also regulated by KLF4 and KLF2. It is
currently unclear exactly how the statins interact with the
MEK5 pathway.
Oxidative stress to endothelial cells can induce an inflam-
matory phenotype and senescence, and previous studies
have shown that statins regulate the redox state of endo-
thelial cells in vitro. Ota et al. [11] report that statins
block oxidative stress-induced endothelial senescence by
enhancing expression of eNOS, Sirtuin (SIRT)1 and
catalase via an AKT-dependent pathway. In a novel
randomized, double-blind clinical study, Antoniades
et al. [12] assessed the redox state of saphenous vein
segments (SVSs) from statin-treated or control patients
undergoing coronary artery bypass grafting (CABG).
They found that short-term treatment with atorvastatin
40mg per day before CABG improves redox state in
SVS, by inhibiting vascular Rac1-mediated activation
of NADPH-oxidase, independently of LDL levels.
These antioxidant effects of atorvastatin were reversed
by mevalonate, and support the notion that even in
patients with relatively low LDL, statins have direct
beneficial antioxidant effects on blood vessels.
Interleukin (IL)-6 is a signature cytokine of innate
immune responses, which stimulates hepatic acute phase
reactant synthesis, including C-reactive protein (CRP).
TheIL-6receptorsignals throughtheJanuskinase/signal
transducer and activator of transcription 3 (JAK/STAT 3)
pathway, although there is only a small literature on the
effects of statins on JAK/STAT signaling. A recent study
by Jougasaki et al. [13] demonstrated that statins block
the effects of IL-6 on human aortic endothelial cells by
preventing the induction of the chemokine monocyte
chemotactic protein-1 and monocyte chemotaxis. These
effects were dependent on blocking mevalonate and
geranylgeranyl pyrophosphate synthesis. Of particular
interest, statins suppressed IL-6-induced phosphoryl-
ation of JAK1, JAK2, tyrosine kinase 2, STAT1 and
STAT3. In addition, STAT3 siRNA attenuated the
ability of IL-6 to enhance monocyte migration. However,
the connections between protein isoprenylation and the
JAK/STAT pathway were not clarified.
Arguably the most important disorder attributable to an
excessive innate immune response is sepsis. In 2004,
Merx et al. [14] reported robust beneficial effects of
simvastatin in a mouse model of bacterial sepsis, and
their data suggested that decreased monocyte adhesive-
ness to endothelial cells was a key mechanism. However,
neither definitive randomized trials nor mechanistic
studies have been performed to further address if and
how statins might reduce the severity of clinical sepsis.
Recently, Rosch et al. [15??] evaluated how statins may
protect against the progression of pneumococcal pneu-
monia to lethal sepsis, which is a frequent problem in the
setting of sickle cell disease (SCD). They found that
simvastatin therapy (1mg/g intraperitoneally per day)
significantly reduced lung and blood bacterial counts
and mortality in a mouse model of SCD after intranasal
pneumococcal challenge. Importantly, statin treatment
reducedtheexpressionofplatelet-activatingfactor(PAF)
receptor on endothelial and epithelial cells in a mevalo-
nate pathway-dependent manner. The PAF receptor is
known to mediate pneumococcal invasion and is up-
regulated in the chronic inflammatory milieu of SCD.
Because statins retained some protective effect in PAF
receptor-null mice, the investigators looked for other
additional mechanisms and discovered that statins
reduced the cytolytic activity of pneumococcal choles-
terol-dependent cytotoxins, presumably by altering
166
Lipid metabolism
Key points
? Statins have many different effects that diminish
innateandadaptiveimmuneresponses,andthereby
reduce inflammation.
? Inhibition of isoprenoid synthesis through the
mevalonate pathway is a common mechanism for
many but not all of the anti-inflammatory effects
of statins.
? Statins block inflammatory responses of endothelial
cellsandTcells byinducingKruppel-liketranscrip-
tion factors.
? Clinical trials in which inflammatory biomarkers
were followed support the concept that anti-inflam-
matory effects of statins independent of lipid low-
ering are of clinical benefit.

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membrane lipid rafts. The authors suggested that the
protective mechanisms induced by statins may also be
relevant for bacterial infections in other chronic inflam-
matory settings besides SCD.
There is a complex relationship between innate immu-
nity and the unfolded protein response (UPR) to endo-
plasmic reticulum (ER) stress. Abundant evidence
indicates that chronic ER stress leads to apoptosis of
macrophage foam cells, which promotes atherosclerotic
lesional inflammation [16]. However, recent studies
suggest that the UPR may inhibit innate immunity in
an acute setting and thereby protect against excessive
inflammatory responses to pathogens or other stimuli
[17?,18?]. Of relevance to this review, statins have been
shown to induce the UPR in macrophages [19] and in
developing Caenorhabditis elegans [20?], an organism that
does not synthesize cholesterol. In both studies, the
authors demonstrated that UPR activation was at least
in part dependent on the mevalonate/isoprenylation
pathways.
Plasmacytoid dendritic cells (PDCs) are key mediators
of innate immune responses to viral infections and
autoimmune responses to nucleic acids. Particularly,
stimulation of Toll-like receptors (TLRs) on PDCs
leads to the abundant production of type I interferons
(IFNs), which contribute to the pathogenesis of
systemic lupus erythematosus (SLE) [21]. In a study
by Amuro et al. [22??], statins inhibited IFNa secretion
by TLR-stimulated human blood PDCs from normal
donors, as well as from SLE patients. Mechanistic
analyses suggested that statins reduced generylgener-
ylation of Rho and affected the downstream activation
of IFN regulatory factor 7, a key transcription factor for
type 1 IFN. These findings suggest a new mechanism
beyond those recently reviewed [23], by which statin
therapy could provide an anti-inflammatory benefit to
SLE patients.
Although most of the studies reviewed here indicate that
statins exert immunomodulatory effects by blocking iso-
prenoid synthesis, an interesting body of work reviewed
by Spite and Serhan [24] has shown that statins promote
the generation of 15-epi-lipoxins via S-nitrosylation of
cyclooxygenase (COX)-2. 15-epi-lipoxins provide stop
signals that counter the actions of proinflammatory lipid
mediators during acute inflammatory responses. In a
recent extension of this work, Planaguma et al. [25?]
discovered that lovastatin and simvastatin initiated the
endogenous biosynthesis of the anti-inflammatory and
proresolving mediator 15-epi-lipoxin A4 during inter-
actions between human neutrophils and airway epithelial
cells. These effects were seen both in vitro and with
mucosal inflammation in vivo, and were not blocked
by mevalonate.
Statins effects on cells and responses of the
adaptive immune system
Some of the earliest evidence for pleiotropic effects of
statins focused on experimental autoimmune encephali-
tis,aT-cell-dependentmousemodelofmultiplesclerosis
(MS) [26], which has led to the use of statins in clinical
trials for the treatment of MS and spurred research into
the effects of statins in other T-cell-mediated diseases
[4]. Here, we will discuss some recent contributions to
our understanding of how statins influence T-cell-
mediated responses.
Forkhead box P3 (Foxp3þ) CD4þregulatory T cells
(Tregs) play an essential role in regulating T-cell
responses to both self and foreign antigens. Previous
studies have suggested that statins may enhance Treg
responses by promoting chemokine-dependent recruit-
ment into inflammatory sites [27]. More recent work by
Kagami et al. [28?] indicates that statins may promote the
differentiation of Treg cells in the periphery while block-
ing the differentiation of proinflammatory helper T
(Th17) cells. They demonstrated that statins skew
T-cell differentiation toward Tregs and away from
Th17 cells via a mechanism dependent on protein
geranylgeranylation. Kim et al. [29??] have explored this
issue further and demonstrated that simvastatin syner-
gizes with transforming growth factor-b (TGFb) to
induce the differentiation of mouse Foxp3þTreg cells
from naive precursors in vitro. This effect was also sec-
ondary to blockade of protein geranylgeranylation and
associated with demethylation of the Foxp3 promoter.
Simvastatin was further associated with reduced expres-
sionofinhibitorySmad6 andSmad7, whichinterferewith
Smad3-dependent and Smad4-dependent TGFb signal-
ing. However, the mechanistic link between blocking
protein geranylgeranylation and inducing the inhibitory
Smads was not addressed in this study.
Direct inhibitory effects of statins on T-cell activation
and function, independent of antigen-presenting cells or
Treg, have been reported over the past years, although
the mechanisms involved are not well characterized. The
recent study of Bu et al. [30??] indicates that induction of
KLF2may bethekeytohowstatinsalterT-cellfunction.
KLF2 regulates the expression of molecules essential for
naive T-cell recirculation and maintenance of T-cell
quiescence. Bu et al. showed that statins blocked acti-
vation-induced downregulation of KLF2 in naive mouse
and human T cells and elevated KLF2 expression in
effector T cells, in a mevalonate-dependent fashion.
Furthermore, statins blocked proliferation and T-cell
IFNg expression in a KLF2-dependent manner. In a
mouse model of myocarditis involving adoptive transfer
of heart antigen-specific T cells, statin treatment of
transferred cells had similar effects to ectopic KLF2
Mechanisms for the anti-inflammatory effects of statins Bu et al.
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expression in attenuating disease severity. One possible
mechanism by which statins might enhance KLF2
expression is by inhibiting the mammalian target of
rapamycin complex 1 (MTORC1) activation, a known
inhibitor of KLF2 expression in activated T cells [31]. In
this regard, it is of interest that Ras homolog enriched in
brain (Rheb), an isoprenylated Ras family GTPase, is
required for MTORC1 activation. A recent study has
shown that statin inhibition of Rheb activation blocks
MTORC1 activation in vascular smooth muscle cells
(VSMCs), leading to impaired differentiation [32?]. It
will be of interest to determine if statin induction of
T-cell KLF2 involves inhibition of Rheb-dependent
MTORC1 activation, or if other GTPases are involved.
Statins are known to reduce T-cell cytotoxity in various
in-vitro assays. The number of CD4þT cells with
tumor necrosis factor-related apoptosis-inducing ligand
(TRAIL)-dependent cytotoxic activity against endo-
thelial cells and SMCs are increased in patients with
acute coronary syndrome (ACS), and these cells are
implicated in plaque-destabilization. Sato et al. [33] have
reported that CD4þT cells from statin-treated patients
with ACS were less effective in TRAIL-dependent kill-
ing of endothelial cells than T cells from patients not
treated with statins. In-vitro statin treatment directly
blocked CD4þT-cell-mediated endothelial apoptosis
and reduced T-cell expression of the activation markers
CD69 and TRAIL, which are enhanced on T cells from
ACS patients. These statin effects were mediated
through inhibition of T-cell receptor-induced ERK
kinase.
Evidence from clinical trials addressing
whether statins exert anti-inflammatory
effects independent of cholesterol lowering
CRP is a biomarker of innate immune responses that has
been rigorously established as a risk factor for clinical
cardiovascular disease independent of blood cholesterol
[3]. Peters et al. [34?] analyzed changes in CRP levels in
patients in the Measuring Effects on intima media
Thickness: an Evaluation Of Rosuvastatin (METEOR)
trial [35], which compared rosuvastatin (40mg per day)
with placebo in middle-aged individuals with moderately
elevated cholesterol levels. They found that rosuvastatin
lowered CRP by 36% compared with placebo and that
there was no relation between changes in CRPand LDL-
cholesterol. The Justification for Use of statins in Pre-
vention: an Intervention Trial Evaluating Rosuvastatin
(JUPITER) trial [36] was unique in examining the effi-
cacy of statin therapy (rosuvastatin 40mg per day) for the
primary prevention of cardiovascular events in patients
without hypercholesterolemia but with elevated high-
sensitivityCRP(hs-CRP).TheJUPITERresultsshowed
a significant reduction in cardiovascular risk associated
with statin therapy in this population. In a more recent
analysis of the JUPITER data, Ridker et al. [37??] show
that increasing baseline levels of hs-CRP were predictive
of subsequent major cardiovascular events and that
rosuvastatin caused the greatest reduction in absolute
risk in those patients with the highest hs-CRP levels.
Although not definitive, these data do strongly support
the interpretation that the anti-inflammatory effects of
statins are key to their impact on cardiovascular risk
reduction in a manner independent of cholesterol low-
ering. In contrast, Millar et al. [38] reported that 2 weeks
of high-dose atorvastatin (80mg per day) did not reduce
circulating levels of CRP or other inflammatory markers
in normolipidemic patients nor did the treatment affect
inflammatory responses of blood monocytes ex vivo. The
lack of effect seen in this study suggests that short-term
statin therapy may be insufficient to reduce inflammatory
responses below a normal baseline.
Limitations of current studies
Published studies that address the subcellular mechan-
isms of statin treatment usually rely on in-vitro models
and typically employ concentrations above 1mmol/l,
which is in excess of the submicromolar concentrations
measured in the blood of statin-treated patients. Further-
more, in-vivo studies in mice usually employ weight/
weight statin doses well in excess of those used clinically.
These facts raise legitimate questions about the appli-
cability of the experimental effects seen with statins to
those that might be realized in the clinical setting. None-
theless, the concentrations of statins that are actually
achieved within the relevant cells of treated patients
are not known. By necessity, most in-vitro and animal
studies only examine the short-term effects of statin
treatment. The use of high concentrations in this setting
may be a legitimate way of detecting influences on
inflammatory pathways that are only exerted at clinically
relevant doses when used over the course of years, rather
than hours or days.
Conclusion
We have discussed recent additions to a robust literature
on the anti-inflammatory effects of statins, which high-
light the diversity of targets in innate and adaptive
immunity (Fig. 1). A common question about the
putative anti-inflammatory effects of clinical statin
therapy is whether or not they are secondary to lipid
lowering. Certainly, the two possibilities are not mutually
exclusive and it is unlikely that clinical trials with statins
will ever be able to answer these questions definitively.
Clearly, a major challenge for investigators will be to
determine which of the many mechanisms by which
statins influence innate and adaptive immunity in
the experimental setting are actually relevant for the
168
Lipid metabolism

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treatment of cardiovascular disease and other immune/
inflammatory disorders.
Acknowledgements
A.H.L. is supported by NIH grants HL087282 and HL56985. G.G. is a
recipient of a fellowship from the Sarnoff Cardiovascular Research
Foundation.
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World Literature section in this issue (pp. 233–234).
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Mechanisms for the anti-inflammatory effects of statins Bu et al.
169
Figure 1 Anti-inflammatory effects of statins
(a) Statins block the mevalonate pathway of cholesterol synthesis, which also synthesizes the isoprenoids geranylgeranyl pyrophosphate and farnesyl
pyrophosphate.TheisoprenoidsarerequiredforthemodificationandfunctionofsmallGTPases(Rho,RacRab,Ras,Rheb),whichareinvolvedinmany
signal transduction pathways in all cell types. A few anti-inflammatory effects of statins that are unrelated to the mevalonate pathway are also shown,
including blocking LFA-1 cell adhesion functions and inducing the synthesis of lipoxins that act to resolve acute inflammation. (b) A selected list of the
many signaling molecules that are modulated by statins blockade of isoprenoid synthesis. In some cases, the statin-impaired GTPases linked to these
downstream molecules are known. (c) Examples of statin effects on cells of the innate and adaptive immune systems, which are discussed in this
review. CDC, cell division cycle; EC, endothelial cell; eNOS, endothelial nitric oxide synthase; ER, endoplasmic reticulum; ERK, extracellular signal-
regulated kinase; HMG, 3-hydroxy-3-methylglutaryl; IFN, interferon; JAK/STAT, Janus kinase/signal transducer and activator of transcription; KLF,
Kruppel-like factor; LFA, lymphocyte function-associated antigen; MAPK, mitogen activated protein kinase; MEK, mitogen-activated ERK kinase;
MTORC, mammalian target of rapamycin complex; NF-kB, nuclear factor-kB; PDC, plasmacytoid dendritic cell; pp, pyrophosphate; ROCK, Rho-
associated coiled-coil containing kinase; UPR, unfolded protein response; VSMC, vascular smooth muscle cell.