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Thymulin: An Emerging Anti-Inflammatory Molecule

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 Curr. Med. Chem. – Anti-Inflammatory & Anti-Allergy Agents, 2005, 4, 333-338 333

Thymulin: An Emerging Anti-Inflammatory Molecule

J.J. Haddada, N.E. Saadéb and B. Safieh-Garabediana,*

a
Department of Biology, Faculty of Arts and Sciences, bDepartments of Human Morphology and Physiology, Faculty of
Medicine, American University of Beirut, Beirut 1107-2020, Lebanon

Abstract: Thymulin is a neuroendocrine hormone with immunoregulatory actions. Originally known as ‘serum thymic
factor’ (FTS), thymulin binds to a carrier protein and zinc (Zn2+) to exert its biologic properties. Thymulin, albeit an es-
sential hormone for the T lymphocyte differentiation and the normalization of the ratio of T-helper cells to suppressor
cells, accumulating evidence suggests its involvement in inflammations of various etiologies. Recently, thymulin has been
shown to have anti-nociceptive effects in hyperalgesia and in pain of neurogenic origin, ostensibly through action on sen-
sory afferents and the release of anti-inflammatory mediators. Given its anti-inflammatory potential, thymulin downregu-
lates the release of inflammatory mediators, such as cytokines and chemokines, upregulates anti-inflammatory factors,
such as interleukin (IL)-10, and exerts molecular control via the regulation of transcription factors and mediators. Recent
evidence tends to indicate that thymulin can be a therapeutic agent in many inflammatory diseases and in pathological
conditions affecting the peripheral and/or the central nervous system. This review discusses current concepts in the anti-
inflammatory actions of thymulin and correlates this activity with an emerging theme for therapeutic treatment.
Keywords: Anti-inflammatory, cytokines, IL-10, immune-therapy, inflammation, neurodegeneration, transcription factors,
thymulin.

1. INTRODUCTION AND BACKGROUND
Thymulin provides an element of the interface in the dis-
crete network established between the neuroendocrine and
immune systems [14,41,73]. The biological activity of thy-
mulin is dependent on equimolar interaction with zinc
(Zn2+). The bio-availability of this ion affects cellular im-
mune effectiveness under physiological and pathophysi-
ological conditions [12,13,51]. It has been shown that thy-
mulin is capable of modulating pro-inflammatory cytokines
in disease [58,63], thereby providing evidence for a novel
anti-inflammatory potential. In addition, thymulin partici-
pates in signaling pathways that mediate genetically-
controlled cell fate and apoptosis [14].
The underlying mechanisms of thymulin-mediated im-
munoregulation are being elucidated.
It has been reported that the effects of thymulin in down-
regulating an inflammatory signal are mediated, at least in
part, by modulating intracellular cyclic nucleotides [44,53].
In addition to the potent anti-inflammatory properties of
thymulin, Zn2+ can synergistically down-regulate a proin-
flammatory signal by reducing the release of inflammatory
mediators [15,51,60] and by acting as a cytoprotective anti-
oxidant in the face of oxidative challenge and stress [22,27].
Furthermore, the anti-inflammatory effect of thymulin is
ostensibly mediated via the up-regulation of IL-10 in vitro
and in vivo [68].
Thymulin represents an emerging theme in anti-
inflammatory therapy, for that particular reason we are dis-
*Address correspondence to this author at the Department of Biology, Fac-
ulty of Arts & Sciences, American University of Beirut, Beirut 1107-2020,
Lebanon; Tel: 961-3-879340; Fax: 1-212-478-1995;
E-mail: bared@aub.edu.lb
cussing current concepts pertaining to the role of this mole-
cule in physiologic and pathophysiologic conditions, with
particular emphasis on its anti-inflammatory and antihyper-
algesic effects.
2. THYMULIN IN INFLAMMATION AND DISEASES
2.1. Role in Neuro-Immune-Endocrine Interactions
Thymic peptides, a heterogeneous family of polypeptidic
hormones synthesized within the thymus, not only exert im-
portant regulatory effects, within both the immune and neu-
roendocrine systems, but are also themselves subject to con-
trol by hormones derived from the hypothalamic-pituitary-
adrenal axis (HPA) and other endocrine glands
[14,57,64,72,74]. Thymulin, a nonapeptide member of this
family originally known as serum thymic factor (FTS)
[11,50], is a critical modulator of immunity and a mediator
of neuro-endocrine interactions [24,64], in addition to regu-
lating immune-related diseases and inflammation [25].
Thymic endocrine function and its fundamental role in
regulating neuroendocrine human diseases have captured a
backlog of interest over the past few decades given the
prowess influence on the immune system. Retrospectively,
an initial report to correlate immunity with thymic peptides
emerged with the role of a circulating thymic factor in self-
recognition and self-tolerance [5]. Moreover, in thymec-
tomized mice, FTS restored colony-forming unit by entry
into DNA synthesis after T-dependent antigen treatment
[31,36]. Restoration of the failing thymic secretion did influ-
ence auto-antibody production, in a manner depending pri-
marily on the auto-antigen eliciting the autoimmune re-
sponse [6,9,82]. In addition, administration of sodium dieth-
yldithiocarbamate (a chelating agent used primarily in the
analytical determination of copper, arsenic, nickel and other

1568-0142/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd.

334 Curr. Med. Chem. – Anti-Inflammatory & Anti-Allergy Agents, 2005, Vol. 4, No. 3
metals) gave evidence for a role of the thymus, and its hor-
mones, in the control and regulation of factors inducing thy-
mocyte differentiation [52,74].
2.2. Role in Disease Modulation
The role of thymulin in disease modulation emanated
from its effect on natural and induced allergy, autoimmunity
and related syndromes. For instance, thymulin exhibited
therapeutic actions in conditions such as ageing [21], Alz-
heimer’s disease (AD) [37], chronic graft-versus-host disease
[4], immune deficiency [7,28], subacute sclerosing panen-
cephalitis [26], myasthenia gravis [39], cancer [25,32,80],
rheumatoid arthritis (RA) [1,17], Down’s syndrome [19,38],
diabetes [84], viral [42,46] and parasitic [34] infections,
drug-induced toxicity [78] and transplantation [8,30,76].
Moreover, the in vivo treatment with synthetic thymulin
ameliorated acute experimental allergic encephalomyelitis
(EAE) with specific restoration of lymphocyte populations
[35]. This was corroborated with thymulin ability to modu-
late inflammatory responses in patients afflicted with multi-
ple sclerosis (MS) [33,45,54].
Perturbations in T cells and T cell subsets of peripheral
blood lymphocytes were also reported in patients with RA
and systemic lupus erythematosus (SLE). For instance, T cell
subsets alterations responsible for abnormal values of the
CD4+/CD8+ immunoregulatory ratio were improved by in
vitro incubation of the lymphocytes with synthetic thymulin
in RA patients [17,18].
Nonetheless, no significant modification occurred for
SLE patients’ lymphocytes, thus supporting the possible
beneficial role of thymulin in the treatment of RA [1].
Moreover, the loss and dysfunction of human post-thymic
precursor cells in SLE were partially corrected with thymulin
administration [49,83]. Several clinical trials for thymulin-
mediated anti-arthritis and anti-SLE have been undertaken
[10,18,75]. The outcome of these studies needs further in-
vestigations.
2.3. Thymulin and Inflammatory Mediators
The thymus gland is a central lymphoid organ where
bone marrow-derived T cell precursors undergo maturation,
eventually leading to the migration of positively selected
thymocytes to T-dependent areas. This process follows under
the influence of the thymic microenvironment, by means of
secretory polypeptides and cell-cell contacts [71]. The
thymic microenvironment is a cellular network composed of
epithelial cells, macrophages (monocytes), dendritic cells,
fibroblasts and extracellular matrix elements, which regulate
key elements in the neuro-immune-endocrine axes.
Cytokines, or the then named ‘biological response modi-
fiers’ [3,29], hold promising avenue for the anti-
inflammatory therapeutic approach of thymulin [21,23]. The
first association emerged with IL-2 and thymulin, which
synergistically enabled autologous rosette-forming T lym-
phocytes to generate helper and cytotoxic functions in nor-
mal [77] and nude [49] mice. Additionally, thymulin pro-
moted IL-2 production in intact and thymus-deprived mice
[81].
Haddad et al.
Interestingly, it has been reported that thymulin could
modulate cytokine release by peripheral blood mononuclear
cells, with implications to SLE [58]. Moreover, interferon
(IFN) production and NK cell activity were enhanced in the
thymulin-treated mice, suggesting that IFN might play an
important role in the induced resistance to pseudorabies virus
(PRV) infection in mice [47]. The in vivo administration of
thymulin prevented D-variant of encephalomyocarditis
(EMC-D) virus-induced diabetes and myocarditis in
BALB/cAJcl mice [43]. This was accompanied by mild de-
generation of the islets of Langerhans and myocardia, and
the conspicuous suppression of inflammation and inflam-
matory mediators. Furthermore, thymulin reduced bleomy-
cin-induced cytokine and chemokine production and inhib-
ited pulmonary fibrosis in mice [86].
Similar results were obtained when NK cell cultures were
incubated in vitro with thymulin prior to assessing cytotox-
icity [40]. Thymulin enhanced the cytolytic activity for NK
cells for several chicken strains and increased the respon-
siveness to NK cells to IFN-? stimulation. This is in concert
with the observation that thymulin could suppress macro-
phage responsiveness to IFN-? [48]. Of note, a suppressor
mechanism of thymulin on TNF-a-induced apoptosis in the
mouse pancreatic β-cell line, via a negative feedback mecha-
nism involving the inhibition of inducible nitric oxide syn-
thase (iNOS) induction, clearly indicated an association be-
tween the antiinflammatory and anti-apoptotic actions of this
peptide [85]. Recently, thymulin was shown to reduce the
hyperalgesia and cytokine up-regulation induced by cutane-
ous leishmaniasis in mice [34].
3. ANTI-INFLAMMATORY ACTIONS OF THY-
MULIN
3.1. Animal Models for Autoimmune Diseases
A conventional example was reported with EAE which
was induced in Hartley guinea pigs and Lewis rats that were
treated with synthetic FTS [35]. Intermittently, clinical
symptoms of acute
EAE were suppressed. Furthermore, histopathological
evaluation showed that the severity of EAE in FTS-treated
guinea pigs was less than in untreated animals. Of note, im-
muno-histochemical examination showed that the numbers
of CD8+, W3/25+, W3/13+ and CD19+ cells in FTS-treated
rats were less than in untreated rats and that the number of
CD8+ cells in FTS-treated rats was greater than in untreated
rats, suggesting that FTS induces CD8+ cells in inflamma-
tory lesions and suppresses inflammation in acute EAE [35].
On the contrary, in a study aimed at restoring decreased T-
cell functions and reduced susceptibility to proteolipid apo-
protein (PLP) induced-EAE in old mice with thymic hor-
mones, thymosin fraction 5 (TF-5) and FTS had no signifi-
cant in vitro and in vivo effect on proliferative responses to
PLP and concanavalin A (Con A), and on EAE induction in
young and old mice [16]. These results suggested that de-
creased T-cell functions cannot be restored by these thymic
hormones, at least in this model of inflammation being in-
vested.
Thymulin Curr. Med. Chem. – Anti-Inflammatory & Anti-Allergy Agents, 2005, Vol. 4, No. 3
3.2. Animal Models for Rheumatoid Arthritis
Thymulin plays a major role in modulating natural and
experimentally-induced arthritis and systemic lupus. For
instance, mice from three different strains (NZB, B/W and
Swan), which spontaneously develop a lupus-like disease
and show a premature decline of their secretion of FTS, were
treated repeatedly with FTS and followed for the evolution
of their autoimmune disease [6]. The autoimmune sialoade-
noitis (Sjogren’s syndrome) appearing in NZB and B/W
mice was completely prevented or even cured by FTS treat-
ment. Furthermore, the increase in anti-erythrocyte auto-
antibody production was transiently delayed in aged NZB
mice. Conversely, anti-DNA antibody production either re-
mained unaffected or was accelerated (in B/W mice) by FTS
treatment, demonstrating that the restoration of the failing
thymic secretion does influence autoantibody production, in
a manner depending primarily on the auto-antigen eliciting
the autoimmune response [6].
In another experimental setup, in collagen induced ar-
thritis (CIA), rats were immunized with bovine type II colla-
gen plus Freund’s incomplete adjuvant, and then thymulin
was administered intraperitoneally on the first day of the first
immunization [2]. Serum thymulin levels in CIA rats were
reported significantly lower than in untreated rats. In addi-
tion, thymulin diminished hind paw swelling (edema) and
onset of arthritis compared with control rats. The serum anti-
type II collagen antibody level was also reduced by thy-
mulin. Of note, histopathological examination showed inhi-
bition of cell degranulation and new bone formation after
injection of thymulin [2]. These results suggest that thymulin
plays a significant role in the onset and development of CIA,
indicating that this peptide may be therapeutically effective
in preventing the development of RA.
3.3. Animal Models for Localized Peripheral/Central In-
flammation and Hyperalgesia
Growing evidence unequivocally support the anti-
hyperalgesic effect of thymulin. This effect is often associ-
ated with the exhibition of anti-inflammatory properties [64].
For example, in a model of peripheral localized inflamma-
tion, induced by intraplantar endotoxin (lipopolysaccharide;
LPS), thymulin reduced inflammatory pain, as measured
with mechanical and thermal hyperalgesia [59,64]. A re-
cently synthesized peptide analogue of thymulin (PAT) was
also reported to have antihyperalgesic and anti-inflammatory
effects [69]. The effect of PAT has extended to implicate
inhibitory effects on pain of neurogenic origin [56].
On the mechanisms mediating the suppression of hyper-
algesia and associated inflammation, it has been observed
that thymulin reversed LPS-induced hyperalgesia by down-
regulating gelatinase activity, a degrading proteinase associ-
ated with certain pathological conditions [79]. In addition,
PAT’s anti-inflammatory ability was attributed, at least in
part, to the down-regulation of pro-inflammatory mediators
[69].
Thymulin treatment, moreover, reversed inflammatory
hyperalgesia and modulated the increased concentration of
pro-inflammatory cytokines induced by intra-cerebroven-
tricular LPS injection, in vivo, thereby providing behavioral
and immunochemical characterization of a rat model for in-
335
tracerebral inflammation and indicates a neuroprotective role
for thymulin in the central nervous system (CNS) [70].
In some models, thymulin anti-inflammatory ability is
exhibited at the level of inducing the release of anti-
inflammatory mediators. Recently, Haddad et al. [22] dem-
onstrated an immunomodulatory potential of thymulin in the
lung perinatal epithelium. In an in vitro model of fetal al-
veolar type II epithelial cells, thymulin selectively amelio-
rated LPS-induced release of IL-1β, but showed no inhibi-
tory effect on IL-6 and TNF-a. Furthermore, Zn2+, pur-
ported as an anti-inflammatory antioxidant, which is required
for the biological activity of thymulin, reduced the secretion
of IL-1β, TNF-a and, to a lesser extent, IL-6 [22]. Of note,
this cation amplified the effect of thymulin on IL-1β and
TNF-a, but not on IL-6. Analysis of whether thymulin is up-
regulating a counterpart anti-inflammatory signaling loop
revealed the involvement of an IL-10-sensitive pathway,
suggesting that thymulin acts as a novel dual immunoregu-
lator by enhancing an anti-inflammatory cytoprotective re-
sponse and depressing an inflammatory signal, an effect syn-
ergistically amplified, in part, by cationic Zn2+ [22].
Recently, we have described a mechanism involving nu-
clear factor-.B (NF-.B), an inflammatory transcription factor
[22], by which thymulin may exert its anti-inflammatory
effect. In a rat model of localized and central hyperalgesia,
thymulin reduced NF-.B DNA-binding activity, ostensibly
via the up-regulation of the cytosolic inhibitor I.B-a by
down-regulating its phosphorylation in vivo [67]. Further-
more, evidence in vitro in dorsal root ganglia neurons
(DRGs) indicated that thymulin antagonizes LPS-induced
secretion of IL-6 and TNF-a, and, interestingly, up-regulates
the release of IL-10 [68]. Moreover, in a rat model of septic
shock, the level of thymulin in serum was increased; how-
ever, it has abolished activity as determined by the Rosette
assay. Assessment of the possible mechanisms revealed that
LPS depletes Zn2+, thus explaining the inactive thymulin
despite its high concentration. Adding extracellular Zn2+
restores the activity of thymulin. On the other hand, ablation
of capsaicin sensitive primary afferents prevented the in-
crease of thymulin level by LPS, which suggests the in-
volvement of neuroendocrine loop mediating the effects of
septic shock on thymulin [65].
Despite the conspicuous anti-inflammatory, analgesic
effects of thymulin, it is noteworthy to mention that this
peptide, at low concentrations, can intriguingly induce oppo-
site effects. For instance, intraperitoneal injection of thy-
mulin to rats caused a significant reduction in both mechani-
cal (paw pressure test) and thermal (hot plate and tail flick
tests) nociceptive thresholds and increased IL-1β level in the
liver [61,62]. Moreover, intraplantar injection of low doses
of thymulin induced hyperalgesia via the up-regulation of
IL-1β, nerve growth factor (NGF) and PGE2 in the skin of
the injected paw [66]. Of particular interest, ablation of cap-
saicin-sensitive primary afferents (CSPA) could alter or
abolish thymulin-induced hyperalgesia [55]. These antago-
nistic effects of thymulin were primarily purported to be
physiologic rather than inflammatory per se [64].
The possible neuro-immune-endocrine mechanisms un-
derlying the anti-inflammatory and the anti-hyperalgesic
effects of thymulin are schematized in Fig. 1.
336 Curr. Med. Chem. – Anti-Inflammatory & Anti-Allergy Agents, 2005, Vol. 4, No. 3 Haddad et al.

Fig. (1). A schematic diagram of the role of thymulin in regulating neuro-immune endocrine actions. The anti-inflammatory role of thymulin
involves several messenger overlaps between the nervous, immune and endocrine systems.
System System; System; Thymulin; CRH; Thymicpeptides; Interferons; Endorphins; ACTH; TNF-α; ILs; Interferons; Endorphins; TNF-α;
SP; Somatostatin; ILs; Central Nervous Endocrine; Immune; Thymic peptides; Interferons; Endorphins; ACTHAnti-inflammatory

4. SUMMARY AND CONCLUSION EAE = Experimental allergic encephalomyelitis

The nervous, immune and endocrine systems communi- GH = Growth hormone
cate through multiple common messengers. Over evolution- iNOS = Inducible nitric oxide synthase
ary time, integrated defense systems have developed to coor-
dinate these communications for specific contexts, including IGF = Insulin-like growth factor
the stress response, acute-phase response, nonspecific im- IFN = Interferon
mune response, immune response to antigens, immune toler-
ance, time-dependent sensitization, neurogenic switching IL = Interleukin
and traumatic dissociation. Thymulin, a tri-dimensional LPS = Lipopolysaccharide
communicator (neuro-immune-endocrine decipher), is an
essential corner stone in the evolution of an integral immune MT = Metallothionein
system and a functional immune response. With its emerging NK = Natural killer
role as an antiinflammatory decoder, thymulin may well
serve the grounds of establishing an intervention therapy, PAT = Peptide analogue of thymulin
especially for diseases affiliated with neurogenic inflamma- PRL = Prolactin
tion. Research continues apace for better fathoming the in-
PLP = Proteolipid apoprotein
teresting, yet intriguing, burgeoning role of thymulin in anti-
inflammatory therapy. PRV = Pseudorabies virus
RA = Rheumatoid arthritis
ACKNOWLEDGEMENTS
FTS = Serum thymic factor
This work was supported by grants from the Lebanese
National Council for Scientific Research (LNCSR), the SLE = Systemic lupus erythematosus
Franco-Lebanese Project CEDRE and the University Re- TF-5 = Thymosin fraction 5
search Board (URB).
TNF. = Tumor necrosis factor
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Received: July 30, 2004 Accepted: February 02, 2005

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