Leptin in the regulation of immunity inflammation and hematopoiesis by alicejenny


									Leptin in the regulation of immunity, inflammation, and
            Giamila Fantuzzi* and Raffaella Faggioni†
            *Department of Medicine, University of Colorado Health Sciences Center, Denver; and †Metabolism Section,
            Department of Veterans Affairs Medical Center, University of California, San Francisco

Abstract: Leptin, the product of the ob gene, is a                 levels directly correlate with adipose tissue mass. Leptin re-
pleiotropic molecule that regulates food intake as                 verses the obesity syndrome of ob/ob mice and results in
well as metabolic and endocrine functions. Leptin                  decreased food intake and increased activity when adminis-
also plays a regulatory role in immunity, inflamma-                 tered to normal mice [4 – 6]. The leptin receptor (OB-R) was
tion, and hematopoiesis. Alterations in immune                     identified shortly after the discovery of leptin itself [7]. The
and inflammatory responses are present in leptin-                   OB-R was found to be the product of the db gene and db/db
or leptin-receptor-deficient animals, as well as dur-               mice were shown to be resistant to leptin [8]. The obese
ing starvation and malnutrition, two conditions                    phenotype of Zucker fa/fa rats is also due to a mutation of the
characterized by low levels of circulating leptin.                 OB-R [9].
Both leptin and its receptor share structural and
functional similarities with the interleukin-6 family
of cytokines. Leptin exerts proliferative and anti-
apoptotic activities in a variety of cell types, includ-           LEPTIN IS A PLEIOTROPIC MOLECULE
ing T lymphocytes, leukemia cells, and hematopoi-
etic progenitors. Leptin also affects cytokine pro-
duction, the activation of monocytes/macrophages,                  The most important role for leptin is considered to be its
wound healing, angiogenesis, and hematopoiesis.                    inhibitory effect on appetite. However, both leptin-deficient
Moreover, leptin production is acutely increased                   (ob/ob) and leptin-receptor-deficient (db/db) mice are not only
during infection and inflammation. This review fo-                  obese. They also develop a complex syndrome characterized
cuses on the role of leptin in the modulation of the               by abnormal reproductive function, hormonal imbalances,
innate immune response, inflammation, and                           and alterations in the hematopoietic and immune system. Sim-
hematopoiesis. J. Leukoc. Biol. 68: 437– 446;                      ilar alterations have been described in leptin-deficient hu-
2000.                                                              mans [10].
                                                                      The syndrome of ob/ob and db/db mice closely resembles the
Key Words: lymphocytes cytokines angiogenesis metabolism           adaptive response to starvation. In the fed state there is a direct
endocrinology                                                      relationship between leptin levels and body fat mass. With the
                                                                   onset of starvation, leptin levels fall rapidly, disproportionally
                                                                   to changes in adipose tissue mass [11]. This fall in leptin levels
THE DISCOVERY OF LEPTIN AND ITS                                    is a signal for the brain to initiate the adaptive response to
RECEPTOR                                                           starvation. Ob/ob and db/db mice exist in a state of perceived
                                                                   starvation and, as a consequence, become obese when given
In the late 1950s, a genetic defect that caused a severely obese   free access to food. Endocrine changes of starvation include
phenotype due to overeating and decreased energy expenditure       suppression of reproductive and thyroid function and stimula-
was identified in mice [1]. The gene was named ob and the           tion of the hypothalamus-pituitary-adrenal axis [11]. Starvation
obese mice carrying the mutation were called ob/ob [2]. Para-      is also associated with marked abnormalities of the immune
biotic animal experiments suggested that ob/ob mice were           response [12]. When caloric intake is adequate and energy
unable to produce a satiety factor, but could respond to such a    stores are normal, leptin levels increase, allowing a permissive
factor from a parabiotic mate. Similar experiments were per-       role on metabolic, endocrine, and immune functions.
formed in db/db mice, which have a mutation in the db gene
and display a phenotype very similar to that of ob/ob mice.
Db/db mice produced the factor missing in ob/ob mice, but
could not respond to it. It was therefore hypothesized that the
db gene encoded for the ob receptor. In 1994, the molecular
defect responsible for the obesity syndrome in ob/ob mice was
                                                                      Correspondence: Giamila Fantuzzi, Ph.D., Department of Medicine, Univer-
identified [3]. The 16-kDa protein encoded by the ob gene was       sity of Colorado Health Sciences Center, 4200 East Ninth Avenue B168,
named leptin, from the Greek leptos ( ε os), meaning thin.         Denver, CO 80262. E-mail: Giamila.Fantuzzi@UCHSC.edu
Leptin is primarily produced by adipose tissue and circulating        Received June 2, 2000; accepted June 2, 2000.

                                                                    Journal of Leukocyte Biology Volume 68, October 2000 437
Fig. 1. Structural similarities between OB-R and the gp130-related family of cytokine receptors. One molecule of leptin binds to one OB-R. The formation of a
tetrameric complex composed of two receptors and two molecules of leptin is required for signaling. Filled boxes represent conserved class 1 cytokine receptor
family domains that are present in each member of the gp130-related family of cytokine receptors. With the sole exception of the short form of OB-R, every other
member of the family activates the JAK/STAT pathway of signal transduction.

LEPTIN AND ITS RECEPTOR: STRUCTURE,                                               induced conformational change rather than from dimerization
TISSUE DISTRIBUTION, AND SIGNAL                                                   of the receptor [21, 22].
TRANSDUCTION                                                                         Several alternatively spliced isoforms of the OB-R have been
                                                                                  cloned [23]. The weight-regulating effects of leptin are medi-
Both the structure of leptin and that of its receptor suggest that                ated through the long form of the OB-R (OB-Rb) in the hypo-
leptin should be classified as a cytokine [13, 14]. In fact, leptin                thalamus [24]. As indicated in Table 1, OB-Rb is also present
and its receptor share structural and functional similarities                     in several peripheral tissues. In particular, endothelial cells,
with members of the long-chain helical cytokines, which in-                       platelets, CD4 and CD8 T lymphocytes, CD34 cells, the
clude interleukin (IL)-6, IL-11, IL-12, leukemia inhibitory                       yolk sac, and the fetal liver express OB-Rb as do leukemia
factor (LIF), granulocyte-colony stimulating factor (G-CSF),                      cells, particularly those of patients with primary acute myeloid
ciliary neurotrophic factor (CNTF), and oncostatin M (OSM). In                    leukemia [25–30].
particular, despite the absence of sequence similarities, a                          Different short isoforms of the OB-R exist. The OB-Ra is the
four-helix bundle structure is present both in leptin and in the                  predominant OB-R found in most tissues and cells, including
members of the long-chain helical cytokine family [14].
   Although white adipose tissue is the major site of leptin gene
expression [3], constitutive leptin mRNA has been detected in                      TABLE 1.         Peripheral Expression of the Long Form of the Leptin
placenta trophoblasts and amnion cells, in the human chorio-                                                    Receptor, OB-Rb
carcinoma cell line BeWo, and in a number of tissues in the
                                                                                  Organ, tissue, or cell type                                       References
fetal mouse, including bone and cartilage [15, 16]. Leptin
mRNA is also selectively transcribed in specific areas of the                      Yolk sac                                                        [27,   31]
brain and pituitary in the rat and in a glioblastoma cell line                    Early fetal liver                                               [27,   31]
[17]. It is interesting that abnormalities in brain development                   Bone marrow                                                     [31]
                                                                                  Spleen                                                          [31]
are present in ob/ob mice, suggesting that leptin is required for                 CD34 cells                                                      [27,   31]
normal neuronal and glial maturation [18]. Finally, leptin                        CD4 and CD8 lymphocytes                                         [28,   29]
expression has been detected in rat gastric epithelium and in                     Platelets                                                       [26]
the glands of the gastric fundic mucosa [19].                                     Endothelial cells                                               [25,   32, 33]
   The leptin receptor (OB-R) is related to class I cytokine                      Leukemia cells (particularly primary AML)                       [30]
                                                                                  Kidney                                                          [16,   23]
receptors, which includes gp-130, the common signal trans-                        Lung                                                            [23,   34]
ducing component for the IL-6-related family of cytokines [13]                    White and brown adipocytes                                      [35,   36]
(Fig. 1). The 840-amino-acid extracellular domain of OB-R                         Marrow stromal cells                                            [37]
contains motifs typical of the hemopoietin receptors, particu-                    Myotubes                                                        [38]
larly a fibronectin type III domain and two hemopoietin do-                        Pancreatic cells                                                [39,   40]
                                                                                  Enterocytes (jejunum)                                           [41]
mains [20]. Leptin receptors form homodimers, both in the                         Anterior pituitary                                              [42]
presence and absence of ligand [21]. Each leptin receptor                         Leydig cells                                                    [43]
binds one molecule of leptin, resulting in a tetrameric complex                   Granulosa and thecal cells of the ovary                         [44]
composed of two receptors and two leptin molecules. However,                      Mammary gland during pregnancy and lactation                    [45]
activation of the receptor is thought to result from a ligand-                    Placental syncytiothrophoblasts                                 [46]

438    Journal of Leukocyte Biology Volume 68, October 2000                                                                           http://www.jleukbio.org
kidney, lung, liver, spleen, and macrophages [7]. Leptin is a          68]. In each model studied, the up-regulation of leptin is
relatively large protein that would ordinarily be inaccessible to      transient and occurs early after administration of the inflam-
the brain. However, it is transported through the blood-brain          matory stimulus. The kinetics of leptin production during in-
barrier via a saturable transport system likely mediated by            fection and inflammation resembles that of cytokine induction.
OB-Ra, which is highly expressed in the choroid plexus [7, 47].           As outlined above, results obtained in animal experiments
Although transfection experiments suggest that OB-Ra may               indicate an acute up-regulation of leptin during infection or
have signaling capabilities, no definitive demonstration of the         inflammation. However, data obtained in human studies do not
signaling role of this receptor has been reported. The OB-Ra           always agree with results obtained in rodents. Although the
may be either a signaling receptor or function as a decoy              administration of IL-1 or TNF- results in increased serum
receptor, similar to the IL-1R type II [48]. The internalization       leptin levels in healthy volunteers [69, 70], LPS injection to
patterns of the short OB-R suggest a role in the intracellular         humans did not lead to an increase in leptin as it did in mice
transport and degradation of leptin inside lysosomes [49].             and hamsters [71–73]. Results from studies conducted in sep-
   Leptin circulates in both a bound and a free form [50]. In          tic patients are also contradictory: either increases [74, 75] or
lean persons, roughly 50% of leptin is present in the bound            no changes [76] in leptin levels during sepsis have been
form, whereas mostly free leptin is present in the circulation of      reported. In contrast, two different studies demonstrated a
obese people [50]. The OB-Re isoform is a soluble receptor             positive correlation between leptin levels and survival after
[51]. The function of OB-Re has not been fully characterized.          sepsis [74, 77]. However, no correlation between leptin levels
Similar to the IL-6 receptor, OB-Re may act as a carrier               and disease activity and no increase in serum leptin levels
protein, delivering leptin to the membrane signaling receptor(s)       have been found in patients affected by rheumatoid arthritis,
[52]. Alternatively, similar to the soluble receptors for IL-1 or      inflammatory bowel disease, or in HIV-infected individuals
tumor necrosis factor, it may function as an inhibitor of leptin       [78 – 81]. In chronic obstructive pulmonary disease, circulating
activity [53, 54].                                                     leptin levels have been reported to be either physiologically
   The OB-Rb isoform contains a 302-amino-acid cytosolic               regulated or related to the inflammatory status [82, 83]. Fur-
domain that includes binding motifs associated with the acti-          thermore, in patients affected by chronic heart failure, either
vation of the JAK/STAT signaling pathways. OB-Rb has sig-              increased or inappropriately low plasma leptin levels have
naling activities similar to those of the IL-6-type cytokine           been reported [84, 85]. More consistent data exist on the
receptors [24]. Leptin activates STAT-1, -3, and -5 after en-          association of circulating leptin levels with hypertension, par-
gaging to the long, but not the short receptor isoforms [55, 56].      ticularly essential hypertension, independent of body mass
In a variety of in vitro systems, leptin activates the MAPK            index [86 – 89].
pathway [40, 57] and induces expression of suppressor of                  It should be noted that the studies reported above analyzed
cytokine signaling (SOCS)-3 [58]. SOCS-3 is a member of a              only systemic circulating leptin levels. However, as with other
family of cytokine-inducible signaling inhibitors [59]. Trans-         regulators of the inflammatory response, leptin function may be
fection data suggest that SOCS-3 acts as an inhibitor of leptin        modulated by local leptin concentration, the ratio between free
signaling [58].                                                        and bound leptin, the expression of different forms of the
                                                                       receptors, the ratio between signaling and non-signaling recep-
                                                                       tors, and the presence of specific inhibitors. These factors all
REGULATION OF LEPTIN PRODUCTION                                        have to be taken into account to evaluate the possible role of
DURING INFECTION AND INFLAMMATION                                      leptin in human disease. For example, although total circulat-
                                                                       ing leptin levels increase significantly in pregnant women, this
Leptin is constitutively produced by adipose tissue and is             is mostly due to a rise in bound leptin, with no alterations in the
present in nanogram concentrations in the systemic circula-            levels of free leptin [90].
tion; its levels are regulated by a variety of factors, particularly
food intake and the endocrine system [for review see refs. 60,
                                                                       Leptin and the anorexia of inflammation
61]. However, the innate immune system also plays a major              Anorexia is commonly associated with local or systemic in-
role in the regulation of leptin production.                           flammatory conditions [91]. Leptin decreases food intake and
   In experimental animals, leptin levels are acutely increased        leptin levels are elevated in experimental models of infection
by inflammatory stimuli, such as endotoxin [lipopolysaccharide          and inflammation. Therefore, it was quite obvious to hypothe-
(LPS)] and turpentine, and by the administration of proinflam-          size that leptin could mediate the anorexia of inflammation.
matory cytokines such as tumor necrosis factor (TNF- ) and             However, leptin is not responsible for the anorexia induced by
IL-1 [62– 64]. Endogenous IL-1 plays a critical role in the            administration of LPS, TNF- , or turpentine in mice. In fact,
induction of leptin by LPS or turpentine because the rise in           no correlation between anorexia and leptin levels during in-
leptin after administration of LPS or turpentine is absent in          flammation has been observed [64, 66]. Moreover, ob/ob mice
IL-1 -deficient mice [64]. Similar results have also been re-           and fa/fa rats are even more susceptible to LPS-, TNF- -, or
ported in rats pretreated with soluble IL-1 receptors, which           IL-1-induced anorexia than their lean littermates [92–94]. In
inhibit IL-1 activity [65]. Endogenous TNF- contributes to             addition, leptin does not seem to be responsible for tumor-
the up-regulation of leptin production observed during bacte-          induced anorexia in rat models of hepatoma and lung carci-
rial peritonitis in mice [66]. In rats, elevated leptin levels are     noma [95]. Therefore, in animals leptin is not responsible for
present during infection with the nematode Nippostrongylus             the anorexia of inflammation. In addition, no correlation be-
brasiliensis and in the course of intestinal inflammation [67,          tween leptin and cachexia has been reported in patients af-

                                                                                   Fantuzzi and Faggioni Leptin and immunity         439
fected by chronic heart failure, AIDS, or cancer [80, 81, 85,        that leptin deficiency is associated with an increased sensitiv-
96].                                                                 ity to LPS-induced toxicity (see below).
   However, a link between leptin-induced anorexia and the              In ob/ob mice, administration of T cell-activating stimuli
cytokine system exists. Luheshi and colleagues demonstrated          leads to a markedly reduced production of TNF- and IL-18,
that administration of leptin increased levels of IL-1 in the        but not of IL-12 and IFN- [104]. This decreased production of
hypothalamus in the rat. The effect of leptin on food intake and     TNF- and IL-18 is associated with protection from T cell-
body temperature was abolished by administration of the IL-1         mediated liver toxicity and is probably due to the T cell atrophy
inhibitory protein IL-1 receptor antagonist (IL-1Ra) and was         observed in ob/ob mice (see below).
absent in IL-1 receptor-deficient mice [97]. It thus appears that        Despite its structural and signaling similarities with the IL-6
some of the effects of leptin in the central nervous system are      family of cytokines, leptin does not induce an acute-phase
mediated through activation of the IL-1 system, a typical            response when administered to mice. However, at the dose of 5
feature of the inflammatory response.                                 mg/kg, leptin augments IL-1-induced corticosterone and IL-6
                                                                     production, two effects typically observed after administration
                                                                     of different members of the IL-6 family [105, 106].
EFFECTS OF LEPTIN ON IMMUNITY,                                       Effects on phagocytic function
                                                                     Only a few studies report on the role of leptin in the regulation
Regulation of cytokine production by leptin                          of phagocytosis. In vitro, leptin enhances the phagocytic activ-
                                                                     ity of murine peritoneal and bone marrow-derived macrophages
Leptin directly regulates the production of several cytokines in
                                                                     against Leishmania major and Candida parapsilopsis [31, 98].
vitro. Lord and colleagues reported a major role for leptin in the
                                                                     Accordingly, the phagocytic function of Kupffer cells is de-
modulation of T cell-derived cytokines [28]. Leptin increased
                                                                     creased in fa/fa rats [102]. However, a different report dem-
IL-2 and interferon- (IFN- ) production while decreasing
                                                                     onstrated increased superoxide and hydrogen peroxide produc-
IL-4 levels, in the course of a mixed lymphocyte reaction
                                                                     tion, as well as augmented cyclooxygenase-2-dependent pro-
(MLR). Therefore, leptin may play an important role in the
                                                                     duction of prostaglandin E2 in macrophages obtained from
regulation of the T helper (Th)1/Th2 balance. Leptin also
                                                                     ob/ob mice [107]. These data suggest that leptin may actually
modulates cytokine production from monocytes/macrophages.
                                                                     down-regulate the activation of monocytes/macrophages.
An increase in LPS-induced production of TNF- , IL-6, and
IL-12 in murine peritoneal macrophages and human monocytes           Proliferative and anti-apoptotic activities
has been reported [98, 99]. In addition, leptin both induces and
up-regulates production of IL-1Ra in the murine macrophage           Leptin displays proliferative and anti-apoptotic effects in a
cell line RAW 264.7 [100]. Furthermore, leptin induces               variety of cell types. In vitro, leptin enhances the alloprolif-
mRNA expression for transforming growth factor (TGF- ) in            erative response of human peripheral blood lymphocytes by
rat glomerular endothelial cells [32]. In human umbilical vein       acting on T lymphocytes [28]. Naive and memory T cells are
endothelial cells (HUVEC), leptin induces production of the          differentially affected by leptin, which mainly regulates pri-
chemokine monocyte chemoattractant protein-1 (MCP-1)                 mary T cell responses. For example, T cells from umbilical
[101].                                                               cord blood are activated by leptin, whereas the presence of
   In vivo, the role of leptin in the regulation of cytokine         memory T cells in an MLR reduces the enhancing effect of
production has been studied primarily in leptin-deficient mice        leptin on proliferation [28]. Leptin also enhances phytohemag-
(ob/ob) and in leptin receptor-deficient mice (db/db) and rats        glutinin- and concanavalin A-induced proliferation of human T
(fa/fa) injected with LPS. Either increased, decreased, or un-       lymphocytes and increases the expression of the activation
changed levels of TNF- have been observed in ob/ob mice and          markers CD69, CD25, and CD71 in both CD4 and CD8
fa/fa rats compared to their lean littermates [98, 100, 102].        cells [29]. Leptin exerts anti-apoptotic activities on murine
IL-6 production was slightly decreased in both ob/ob mice and        thymocytes cultured in the presence of dexamethasone [108],
fa/fa rats, whereas levels of IL-1 , IFN- , and the chemokine        possibly through the maintenance of Bcl-2 expression [109].
macrophage inflammatory protein 1 were not affected by                Similar to IL-6, a role for STAT-3 activation is likely in the
leptin deficiency [98, 100, 102]. Serum IL-10 and IL-1Ra              proliferative and anti-apoptotic effects of leptin [110]. The role
levels were decreased in ob/ob mice injected with LPS, as was        of leptin in the regulation of proliferation and apoptosis of T
the hepatic expression of IL-10 and IL-12 in LPS-treated fa/fa       lymphocytes is instrumental in the development of the T cell
rats [100, 102]. In a study evaluating the hepatic response of       atrophy of ob/ob and db/db mice (see below).
ob/ob mice to the administration of P. acnes and LPS, increased         Leptin stimulates proliferation of cultured tracheal epithelial
hepatic expression of IL-12, IL-18, and IFN- associated with         cells, lung squamous cells, and embryonic and pancreatic cell
reduced levels of IL-4 and IL-10 was reported [103]. The             lines [34, 40, 57]. A role for leptin in glomerulosclerosis is
disparate results obtained in in vivo experiments evaluating the     suggested by its stimulatory effect on glomerular endothelial
role of leptin in the cytokine response to LPS are likely due to     cell proliferation, particularly in the presence of angiotensin II
differences in the models studied (high- versus low-dose LPS,        [32].
pre-sensitization models versus direct administration, etc.).           Leptin has proliferative and anti-apoptotic activities in leu-
However, despite the lack of agreement on the role of leptin in      kemic cells, which express the long and short forms of OB-R
cytokine production after LPS administration in vivo, it is clear    [30, 111]. In primary acute myeloid leukemia cells, leptin

440   Journal of Leukocyte Biology Volume 68, October 2000                                                      http://www.jleukbio.org
induces low-level proliferation and increases proliferation in-      LEPTIN DEFICIENCY CAUSES A
duced by GM-CSF, IL-3, and stem-cell factor (SCF), while             DYSREGULATION OF THE IMMUNE AND
reducing apoptosis induced by cytokine withdrawal in MO7E            INFLAMMATORY RESPONSE
and TF-1 cells [30].
                                                                     As indicated above, a multifactorial syndrome characterized by
Hematopoiesis                                                        obesity, diabetes, infertility, and various hormonal imbalances
                                                                     is present in ob/ob and db/db mice and in fa/fa rats. Dysregu-
That leptin may participate in the regulation of hematopoiesis       lation of the immune and inflammatory response is also ob-
is suggested by the alterations observed in ob/ob and db/db          served in these animals and is primarily characterized by
mice. Colony-forming assays demonstrate a deficit in lympho-          reduced T cell numbers, altered responsiveness of the mono-
poietic progenitors in db/db mice, which are also unable to          cyte/macrophage system, and impaired wound healing (Fig. 2).
completely recover their lymphopoietic populations after an
irradiation insult [112]. Db/db mice also have defective eryth-      T lymphocytes
rocyte production in the spleen, although the concentration of
                                                                     Consistent with the proliferative activity of leptin on T cells,
peripheral blood erythrocytes is normal [112]. A decrease in
                                                                     thymic atrophy is present in ob/ob and db/db mice and in fa/fa
the number of circulating lymphocytes and an increase in
                                                                     rats [108, 117–121]. A decrease in the number of circulating
monocytes is present in ob/ob mice [104]. Furthermore, a
                                                                     lymphocytes and an increase in monocytes is also present in
correlation between leptin levels and leukocyte counts in hu-
                                                                     ob/ob and db/db mice [104, 122]. In addition, the number of
mans has been reported [113, 114].
                                                                     CD4 NK T cells is selectively reduced in the liver of ob/ob
   A direct role for leptin in hematopoiesis has been suggested      mice [103]. The ability of leptin to protect leptin-deficient
based on the expression of OB-Rb in yolk sac, fetal liver, bone      animals from thymic atrophy probably involves a direct anti-
marrow, and CD34 cells, as well as lympho-hematopoietic,             apoptotic mechanism [108]. Ob/ob and db/db mice exhibit
fetal stromal, and megakaryocytic cell lines [27, 30, 31, 112].      defective T cell-mediated immunity, as demonstrated by an
However, data on the role of leptin in the direct regulation of      impaired delayed-type hypersensitivity reaction (DTH), sup-
hematopoietic cell proliferation are somewhat contradictory.         pression of skin allograft rejection, and inhibition of footpad
Leptin has been reported to induce granulocyte-macrophage            swelling induced by recall antigens [117, 120]. Furthermore,
colony formation from murine bone marrow cells and to en-            ob/ob mice are protected from liver damage induced by acti-
hance the activity of SCF and erythropoietin [115]. In addition,     vation of T cells and production of TNF- and IL-18 [104].
a proliferative effect of leptin on BAF-3 and on multilineage        Exogenous leptin restores the responsiveness of ob/ob mice to
progenitor cells has been observed [112]. On the other hand,         T cell-activating stimuli and normalizes their lymphocyte and
Gainsford and colleagues [31] were unable to demonstrate a           monocyte populations [104, 108]. It is worth noting that obese
proliferative role for leptin in murine or human marrow cells,       individuals receiving long-term (4 weeks) subcutaneous injec-
even when leptin was used in combination with GM-CSF,                tions of leptin at 0.3 mg/kg/day developed skin reactions
G-CSF, M-CSF, IL-3, IL-6, Flk-ligand, erythropoietin, SCF, or        characterized by erythema, induration, pruritus, and rash at the
thrombopoietin.                                                      injection site (the reactions were milder or absent in subjects
   In conclusion, the demonstration of a direct role for leptin on   receiving lower doses of leptin). The adverse effects were
the proliferation of hematopoietic progenitors is still controver-   severe enough to convince the data monitoring committee of
sial. However, in vivo data strongly suggest a regulatory role,      the clinical trial to halt that part of the study [123]. Although
possibly indirect, for leptin in hematopoiesis, particularly on      not studied during the trial, activation of cell-mediated immu-
the lymphocytic lineage.                                             nity by leptin may have contributed to skin reactions observed
                                                                     at the site of leptin administration.
Angiogenesis and atherogenesis
Endothelial cells express the long form of the OB-R, which           In contrast to the reduced responsiveness of ob/ob and db/db
mediates leptin-induced proliferation [25, 33]. Exposure of          mice to T cell-activating stimuli, an increased sensitivity to
endothelial cells to leptin leads to tyrosine phosphorylation        monocyte/macrophage-activating stimuli is observed in the ab-
of the OB-R and activation of STAT-3 and Erk1/2 [25, 33].            sence of leptin. In particular, ob/ob mice are more susceptible
Both in vitro and in vivo assays demonstrate that leptin has         to LPS- or TNF- -induced lethality than their lean littermates
angiogenic activities, inducing neovascularization and for-          [93, 100]. Ob/ob mice and fa/fa rats also display enhanced
mation of capillary-like structures [25, 33]. However, leptin        hepatotoxicity after administration of LPS [102, 104]. Further-
does not increase angiogenesis in vivo in the skin of ob/ob          more, an enhanced pyrogenic response to IL-1 is present in
mice [116].                                                          fa/fa rats [124]. The mechanism responsible for the increased
   In HUVEC, leptin increases the generation of reactive oxy-        sensitivity of ob/ob mice and fa/fa rats to LPS, TNF- , and IL-1
gen intermediates and MCP-1 by activating JNK, AP-1, and             remains unclear. It should be noted that, in addition to reduced
NF- B pathways, therefore exerting potential atherogenic ef-         thymic and circulating lymphocytes, a fourfold increase in the
fects [101]. Furthermore, leptin promotes aggregation of human       number of circulating monocytes is present in ob/ob mice
platelets when used at concentrations corresponding to those         [104]. In addition, prevention of lymphocyte apoptosis is asso-
observed in obese individuals [26].                                  ciated with improved survival in a murine model of sepsis,

                                                                                 Fantuzzi and Faggioni Leptin and immunity       441
Fig. 2. Immune alterations associated with leptin deficiency or low leptin levels. Effect of exogenous leptin. Reduced numbers of T lymphocytes and suppressed
responsivity to T cell-activating stimuli are present in both leptin-deficient (ob/ob) mice and in starved mice, which have low leptin levels. Under the same
conditions, a hyperresponsiveness of the monocyte/macrophage system is observed. Administration of exogenous leptin alone normalizes most of the observed
immunological abnormalities associated with leptin deficiency or low leptin levels.

suggesting a critical role for lymphocytes in the regulation of                  alterations, which include changes in gonadal, adrenal, and thy-
susceptibility to LPS [125].                                                     roid hormones in male mice and delay in ovulation in female mice
                                                                                 [11]. However, starvation also suppresses the immune system,
Wound healing                                                                    with a particularly marked effect on T cell-mediated responses
Ob/ob and, particularly, db/db mice spontaneously develop a                      [128 –130] (Fig. 2). Reduced thymus weight and IL-2 production,
syndrome resembling type 2 diabetes. One characteristic of                       associated with increased susceptibility to infections, are charac-
this syndrome is impaired wound healing. Both ob/ob and db/db                    teristically observed in malnourished individuals [129, 131, 132].
mice show a delayed dermal healing response [126, 127].                          Increased susceptibility to infections has also been reported in
Although the cause of this impairment is not clear, cellular                     leptin-deficient individuals [10]. Malnutrition also leads to wound
infiltration, formation of granulation tissue, and neovascular-                   healing impairment and, possibly, to hyperactivation of the mono-
ization are reduced in db/db mice compared with their wild-                      cyte/macrophage system [133, 134]. These features of malnutri-
type littermates [127]. Administration of leptin, either system-                 tion also occur in ob/ob and db/db mice, although the susceptibil-
ically or topically, accelerates wound healing in ob/ob mice,                    ity to infection of these animals has not been thoroughly studied as
without affecting angiogenesis [116]. Similar results are ob-                    yet.
tained by administration of basic fibroblast growth factor to                        Most of the neuroendocrine and immune alterations associ-
db/db mice [127].                                                                ated with fasting can be reversed by administration of leptin. In
                                                                                 mice, exogenous leptin prevents suppression of cell-mediated
                                                                                 immunity, development of thymic atrophy, and reverses the
LEPTIN AND THE IMMUNE SUPPRESSION OF                                             increased susceptibility to the lethal effects of LPS or TNF-
STARVATION                                                                       [28, 108, 135].

The multifactorial syndrome observed in ob/ob and db/db mice                     CONCLUSIONS
closely resembles the neuroendocrine-immune response to star-
vation [11]. Leptin levels fall sharply with the onset of starvation,            Leptin, initially discovered as a regulator of food intake and
and administration of leptin effectively prevents neuroendocrine                 energy expenditure, is emerging as a pleiotropic molecule

442    Journal of Leukocyte Biology Volume 68, October 2000                                                                        http://www.jleukbio.org
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446      Journal of Leukocyte Biology Volume 68, October 2000                                                                          http://www.jleukbio.org

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