Gender differences in host defense mechanisms

~

J. psychiat. Res., Vol. 31, No. 1, pp. 99 113, 1997

Pergamon

Copyright

1997Elsevier Science Ltd. All rights reserved Printed in Great Britain 0022 3956/97 $17.00+0.00

Plh S0022-3956(96)00055-6

GENDER

DIFFERENCES JOSEPH

IN HOST DEFENSE

MECHANISMS

G.CANNON and BARBARA A. St. PIERRE

Intercollege Physiology Program and Department of Kinesiology, Pennsylvania State University, Pennsylvania, U.S.A.

(Received 3 August 1995; revised 22 February 1996: accepted 23 September 1996) Summary Extensive studies in both h u m a n s and animals have shown that females express enhanced levels of immunoreactivity compared to males. Whereas this provides females with increased resistance to m a n y types of infection, it also makes them more susceptible to a u t o i m m u n e diseases. This review will focus on gender-related differences in non-specific host defense mechanisms with a particular emphasis on monocyte/macrophage function and a primary product of monocytes: interleukin-1 (IL-1).* I m m u n o m o d u l a t o r y cytokines such as 1L-l are influenced by gender-sensitive hormones, and reciprocally, these cytokines influence gender-specific hormones and tissues. Patients with chronic fatigue syndrome (CFS) are predominantly women, therefore it m a y be useful to look toward gender-specific differences in immune function to find a key for this poorly understood syndrome. ((' 1997 Elsevier Science Ltd.

Historical and clinical observations In 1786, Dr Clarke at the Lying-in Hospital in Dublin reported: observations which have been made on the laws that govern h u m a n mortality prove that the mortality of males exceeds that of females in almost all stages of life... Male foetus's requireing more nutrition than female foetus's, because larger, and also for this reason more liable to injury in delivery, are brought into the world less perfect... (Clarke, 1786)

It is interesting that male inferiority in survival, a fact recognized for at least a century before Clarke (see (Goble & Konopka, 1973)), would be explained by male superiority in body size. Since Clarke's time, numerous clinical studies have demonstrated that immune responsiveness is greater in women than men. But rather than engendering overall survival Correspondence to: J. G. Cannon, 111 Noll Physiological Research Center Pennsylvania State University University Park, PA 16802 6900, U.S.A. Tel: + 1 814 865 0322; fax: + 1 814 865 602. *Interleukin-I has two agonist forms (~ and r) that bind to the same receptors and have virtually identical biological activities. Many of the reports cited in this review used bioassays that do not distinguish between the two forms, therefore the generic term IL-I is used in most cases. Two forms of tumor necrosis factor (TNF) also exist. In this review, T N F always refers to the ~ form (also known as cachectin). Other abbreviations used in this review are: CFS chronic fatigue syndrome; Ig - - immunoglobulin; SLE - - systemic lupus erythematosus; I D D M - - insulin dependent diabetes mellitus; M O - - macrophage(s); T h l , Th2 - - T helper 1, 2; IFN~' - interferon 7; LH luteinizing hormone; FSH - - follicle stimulating hormone; PG - - prostaglandin; C R F corticotrophin-releasing factor; A C T H - - adrenocorticotrophic hormone; H P A - - hypothalamic-pituitary-adrenal; G n R H --- gonadotropin-releasing hormone; P R L prolactin; E - - estrogen; P - - progesterone; DES diethylstilbestrol. 99

100

J.G. Cannon and B. A. St. Pierre Bacterial septicemia Fatal pneumonia/influenza Bacterial meningitis

m • BB

Rheumatoid arthritis IDDM SLE i i 3 2 male/female preponderance

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5 6 7 female/male preponderance

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Figure 1. Relativeincidencesof infection(solid bars) and autoimmunedisease (shaded bars) in men vs women.

Compiled from (Allen, 1934;Ahmedet al., 1985;Centersfor Disease Control, 1992).

superiority, this difference merely changes the relative immunologically-based risks faced by women vs men. As shown in Figure 1, women have less incidence and mortality to several types of infection (Allen, 1934; Centers for Disease Control, 1992). This difference between the sexes in susceptibility to infection was apparent before the advent of antibiotics and vaccines, and seems to have become more pronounced since that time (Washburn et al., 1965). Immunoglobulin M (IgM) levels are higher in adult women (Butterworth et al., 1967) and IgG responses to certain hepatitis B vaccine preparations were three times higher in women than men (Struve et al., 1992). However, the same mechanisms that reduce risks of infection in women may also make them more susceptible to various autoimmune diseases. As shown in Figure 1, incidence rates for systemic lupus erythematosus (SLE), insulin-dependent diabetes mellitus (IDDM) and rheumatoid arthritis are several-fold higher in women than men (Ahmed et al., 1985). Furthermore, there is an association of certain clinical conditions with specific phases of the menstrual cycle. Chlamydial and gonococcal infection rates vary with the menstrual cycle (Sweet et al., 1986; Cohen et al., 1987). Urinary tract infections are less likely to recur if initial onset is in the luteal phase (Leibovici et al., 1989). Likewise, breast carcinoma is less likely to recur if excision is performed during the luteal phase (Senie et al., 1991). Experimental approaches The underlying mechanisms causing gender differences in immune reactivity have been studied by several experimental approaches: (1) treating animals, or immune cells collected from animals, with sex steroids or non-steroidal estrogenic compounds; (2) gonadectomizing animals with or without hormone replacement therapy; (3) observing immunological changes during periods of altered hormonal status (human menstrual cycles, rodent estrus cycles, menopause or pregnancy). As in any field of research, each experimental approach has certain strengths and weaknesses which can sometimes lead to inconsistent results. Responses of isolated cells treated with exogenous hormones can be difficult to interpret if the hormone concentrations are outside the physiological range. Even within the physiological range, dose-response characteristics can be biphasic (Flynn, 1984). Important

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cofactors may be missing from cell cultures, for example, the action of estradiol may vary depending upon whether progesterone is present (Kincade et al., 1994). Gonadectomizing animals not only reduces gonadal steroid concentrations in vivo (the intended result), but dramatically increases gonadotropin levels through loss of steroid feedback inhibition on the pituitary gland. Rodent estrus cycles are much shorter (five days) than human menstrual cycles (28 days), and the timing and sources of estrogen secretion can vary between species. Some of these issues will arise as experimental evidence is discussed in the following sections. The influence of gender-specific hormones on host defense In L,itro experiments have often focused on how leukocyte responses to an antigen or pathogen are influenced by the presence of a gonadal steroid. In vivo however, the steroid, or other hormone, may have multiple influences before a leukocyte and antigen (or pathogen) actually meet. Figure 2 provides a pictorial flow diagram for some of these influences. The circled letters in this figure are keyed to the events described in the next four paragraphs. Several aspects of this figure and discussion were inspired by an excellent review of estrogens and infection (Styrt & Sugarman, 199 l). Initially, gonadal steroids or other gender-sensitive hormones may influence the development of stem cells in the bone marrow into mature leukocytes, such as neutrophils, blood monocytes, tissue macrophages (MO), and lymphocytes ("a" in Figure 2) (Reisner, 1966). Androgens have been shown to stimulate recovery of neutrophil counts in rats after radiation (Horn & Price, 1972), whereas pregnant mice, or mice dosed with estrogens at pregancy levels, had B cell production suppressed to <20% of controls (Kincade et al., 1994). Suppression induced by lower concentrations of estrogen was amplified when

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stem ceils Bone marrow I ;e differentiated leukocytes I

Circulation

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Lymphoid ~ organs -

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-~J~ Peripheral ~'e~ G'~%r~oe~ tissues V'*o~ ~a~oh I ~antigenI macrophsges External environment:

pathogen

Figure 2. Flow diagram of cellular movements and interactions that are influenced by gender-specific hormones. The circled letters are keyed to the text section entitled "The influence of gender-specific hormones on host defense" which provides a detailed description of these events.

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J.G. Cannon and B. A. St. Pierre

combined with progesterone whereas progesterone alone had no effect (Kincade et al., 1994). Since these various classes of leukocytes derive from common precursor ceils in the bone marrow, it is possible that more than one leukocyte type may be affected. Female sex hormones may regulate leukocyte entry into peripheral tissues or secondary lymphoid tissues, such as the thymus and spleen. This process usually requires that cells attach to the endothelium ("b" in Figure 2), alter their shape, and then squeeze between endothelial cells ("c" in Figure 2). Estradiol and progesterone (but not testosterone) caused up to a two-fold augmention of leukocyte attachment in vitro by enhancing tumor necrosis factor-induced expression of membrane intercellular adhesion molecules on human vein endothelial cells (Cid et al., 1994). These hormones may also facilitate leukocyte entry by altering membrane lipid composition. Combinations of estrogens and progestens in oral contraceptives have been shown to alter plasma lipids which in turn affect the sphingomyelin/lecithin ratio in cellular membranes. Mononuclear cells from women taking these contraceptives exhibited a small (5%) increase in membrane fluidity (Bagdade & Subbaiah, 1988). In vitro, supraphysiological concentrations of estrogen reduced neutrophil membrane fluidity, possibly by a physicochemical effect of the steriod on the membrane rather than a receptor-mediated effect in the nucleus (Hammerschmidt et al., 1988). Chemotaxis, the process by which leukocytes are attracted to a site of infection or inflammation, is sensitive to gender-related hormones. The capacity of neutrophils to unidirectionally migrate toward a pathogen through a chemotactic gradient ("d" in Figure 2) was increased by estrogen/progesten compounds (Nilsson et al., 1980). On the other hand, transcription o f m R N A for chemoattractant proteins by MO was decreased 50-90% by estrogen treatment (FrazierJessen & Kovacs, 1995). Neutrophils from hyperprolactinemic patients tended to exhibit suppressed chemotaxis in vitro (Harris et al., 1979). Within secondary lymphoid tissues, lymphocytes undergo further maturation ("e" in Figure 2) that may be directly influenced by steroids, as well as by steroid- or prolactininduced changes in thymic environment or function (Grossman, 1985; Nagy & Berczi, 1991). For example, prolactin promotes thymocyte growth directly and also stimulates thymic epithelial cells to produce the T cell enhancer, thymulin (Nagy & Berczi, 1994). On mature T lymphocytes, prolactin upregulates receptor expression for the growth factor interleukin-2 (IL-2) (Viselli et al., 1991; Tsai & Heppner, 1994). Within T lymphocytes, IL2 and prolactin both appear to act through the same signal transducer and activator of transcription (STAT 5) (Hou et al., 1995; Wakao et al., 1995). Gonadal steroids can also affect the relative virulence of a pathogen. Epithelial cells that make up the physical barrier to the external environment ("f" in Figure 2) can be altered by gonadal steroids so that pathogens can more easily adhere to and ultimately traverse this barrier (Chan et al., 1984). Finally, these hormones can actually alter the replication rates of some microorganisms (reviewed in Styrt & Sugarman, 1991). Lymphocytes Lymphocytes (B cells and certain T cells) mediate specific host defense mechanisms, such as antibody production and cytotoxicity, respectively. Other subsets of the T cell population include a spectrum of helper cells that at one extreme release cytokines which primarily

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augment antibody production (Th2 cells release IL-4, IL-6, IL-10 and others) or at the other extreme promote primarily cytotoxicity (Thl cells release IL-2, IFN7 and others) (Kelso, 1995). Gender-related differences in antibody production, lymphocyte proliferation and cytotoxic activity, and the influence of steroid hormones on these functions have received considerable study and have been extensively reviewed (Grossman, 1985; Grossman et al., 1991; Homo-Delarche et al., 1991). Peptide hormones, including prolactin, luteinizing hormone (LH) and follicle stimulating hormone (FSH) all enhance the proliferation of lymphocytes in response to mitogenic stimuli (Athreya et al., 1993). Adhesion of lymphocytes to thymic epithelium is also enhanced in vitro by prolactin (Savino et al., 1994). As important as the direct influences of gonadal steroids and pituitary peptide hormones on immune cells may be, the indirect effects of these hormones accomplished by altering cytokine production or action may be arguably more pervasive. Reciprocally, cytokines such as IL-1 have considerable influence on the production and action of pituitary and gonadal hormones, to be discussed in detail in a later section of this review. Cellular mediators of non-specific host defense Neutrophils, blood monocytes and tissue MO have several mechanisms of host defense in common, including phagocytosis, cytotoxicity and secretion of inflammatory mediators. Phagocytosis is a process by which a cell engulfs and digests necrotic cells, cellular debris, and antigens, thereby isolating and removing any material that could threaten the host. Cytotoxicity may involve the release of reactive nitrogen intermediates (nitric oxide), reactive oxygen intermediates (hydrogen peroxide, superoxide and hydroxyl radicals), or the secretion of cytotoxic cytokines (e.g., TNF and lymphotoxin). The secretion of inflammatory mediators, such as the proinflammatory cytokines (e.g., IL-1 and TNF) and prostaglandins (e.g., PGE2 and PGI2) serve as part of host defense by recruiting and regulating a variety of inflammatory cell types, which may be necessary to remove or destroy antigen, keep an infection localized, and initiate tissue repair processes. Neutrophils are an early line of cellular defense, recruited to the site of infection or injury within minutes. Women's neutrophils are morphologically distinct, with a characteristic chromatin nodule branching offthe nuclei (Davidson & Smith, 1954). Circulating neutrophil courts are approximately 20% higher in women (Bain & England, 1975a), and the count varies in a cyclic fashion during the menstrual cycle (Bain & England, 1975b) that correlates with urinary estrogen measurements (Cruickshank et al., 1970). Furthermore, the generation of reactive oxygen species was 40% higher and arachidonate metabolite synthesis was seven-fold higher in cells isolated from women and varied in a cyclical manner through the menstrual cycle (Mallery et al., 1986). Arachidonate metabolites, including prostaglandins and thromboxanes, not only have direct inflammatory effects on peripheral tissue but have important immunomodulatory effects on other leukocytes. In the final trimester of pregnancy, generation of reactive oxygen species by neutrophils is reduced approximately 50% (Crouch et al., 1995). Blood monocytes and tissue MO usually arrive at an injured site several hours after neutrophils. Despite differences in their distribution and maturity (MO represent a more mature stage than monocytes), these cells share similar surface membrane markers, and are

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J.G. Cannon and B. A. St. Pierre

capable of performing similar activities (van Furth, 1992). Thus the term " M O function" can be used to refer to activities performed by both blood monocytes and tissue MO. In addition to phagocytosis, cytotoxicity and inflammatory mediator secretion, MO also carry out antigen presentation. In this process, phagocytized antigen is broken down and fragments are brought back to the surface of the MO complexed with certain receptors that serve as an activation signal for lymphocytes. Through exogenous administration and/or gonadectomy, several sex hormones have been associated with changes in MO number and modulation in MO function. Ovariectomy decreases the relative number of MO to 1/6th of baseline whereas replacement therapy with estradiol or progesterone restores normal uterine MO counts (De & Wood, 1990). Estrogen, progesterone, prolactin, and testosterone appear to stimulate MO cytotoxic mechanisms by enhancing the release of reactive oxygen species (Edwards III et al., 1988; Kato et al., 1988; Chen & Johnson, 1993; Chao et al., 1994). In contrast, nitric oxide release is unaffected, or reduced by estrogen, progesterone, and testosterone depending on the concentration (Chao et al., 1994). Peritoneal MO from female rats synthesize a greater amount of prostaglandins than cells from males (Duet al., 1984; Leslie et al., 1987). Phagocytosis by MO from ovariectomized mice is diminished approximately 27-35%, but restored when the ovariectomized animals are treated with estradiol alone and not with progesterone (Nicol & Vernon-Roberts, 1965; Baranao et al., 1991). The in vivo administration of diethylstilbestrol (DES, a synthetic estrogen) or prolactin increases peritoneal MO phagocytosis rates by 50-80% in male and female mice (Boorman et al., 1980; Chen& Johnson, 1993). The role of testosterone in modulating MO phagocytosis is unclear, Castration of male mice reduces MO phagocytosis in vitro by ~30%; however, castration appears to enhance the phagocytosis of necrotic skeletal muscle in vivo (Grounds, 1987; Baranao et al., 1991). MO number and function change according to specific hormonal phases of the menstrual/estrus cycles and pregnancy. Uterine MO counts are approximately 2.5- to 6-fold greater during estrus and early diestrus phases than in the late diestrus and proestrus stages (Huang et al., 1995). However, these changes may represent alterations in tissue distribution rather than a change in absolute MO numbers (De & Wood, 1990). Phagocytic activity is approximately 50% higher during the proestrus/metestrus stages of the estrus cycle compared to the estrus/diestrus stages, in which phagocytic activity is similar to that observed in ovariectomized animals (Nicol & Vernon-Roberts, 1965). In a study involving humans, MO phagocytic activity was increased > 50% throughout pregnancy (Koumandakis et al., 1986). One rodent study also found > 50% increases in MO phagocytic activity during pregnancy (Nicol & Vernon-Roberts, 1965), while another only found decreases of approximately 50% during early pregnancy (Baranao et al., 1992). Prostaglandin production is also affected by hormonal shifts occuring during the menstrual cycle and pregnancy. PGE2 and PGI2 release by stimulated monocytes is greater during the luteal phase than the follicular phase and near ovulation (Flynn, 1984; Polan et al., 1988; Arend et al., 1991). Prostaglandin production by murine peritoneal MO decreases approximately 80% during mid-gestation, followed by increases late in pregnancy, compared with control levels (Baranao et al., 1992). Antigen presentation by MO taken from rat spleens varies by approximately 50% through the course of the estrus cycle (Prabhala & Wira, 1995).

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Gender-specific hormones regulate IL-1 production Gonadal steroids have significant effects on IL-1 production. Peritoneal MO from female rodents produce more IL-1, both spontaneously and after stimulation, than matched males (Hu et al., 1988). Gonadectomy of female rodents diminished IL-1 synthesis by peritoneal MO, whereas estrogen replacement therapy restored synthesis rates (Hu et al., 1988; Da Silva et al., 1993). Peritoneal exudate MO from female mice demonstrate an increase in ILl activity when the mice are treated with continuous infusions of estrogens (e.g., estradiol or DES) or progestens (e.g., progesterone and ethisterone), although no change occurs with the in vivo administration of testosterone (Flynn, 1986). Estradiol stimulates peritoneal MO of male rats to synthesize IL-1, while castration of male mice has no effect on IL-1 synthesis by peritoneal MO (Hu et al., 1988; Da Silva et al., 1993). Sex steroidal hormone modulation of IL-1 production is also evident with human blood monocytes. Blood monocytes from healthy males demonstrated a > 2-fold increase in the secretion of IL-I activity when treated in vitro with low concentrations (10 -8 to 10~° M) of progesterone, whereas higher concentrations (> 10 7 M) of this steroid suppressed IL-l secretion, and 10-SM progesterone completely prevented secretion (Polan et al., 1988). Similar biphasic dose-response relationships exist for estrogen as well as progesterone with respect to IL-I production by human placental MO (Flynn, 1984) and IL-lfl mRNA expression in LPS-stimulated blood monocytes/n vitro (Polan et al., 1989). In contrast to these studies, spontaneous release of IL-1 bioactivity or TNF immunoactivity by blood monocytes collected from women after menopause or oophorectomy (i.e., low gonadal steroid hormone conditions) were reportedly increased >40-fold and 5-fold, respectively (Pacifici et al., 1989; Pacifici et al., 1993). These investigators found a positive relationship between IL-1 production and osteoporosis, and furthermore, found that estrogen/progesterone replacement therapy resulted in reductions in cytokine secretion. Other investigators have not observed a relationship between spontaneous IL-1 secretion and osteoporosis (Hogasen et al., 1995), or found that estrogen replacement therapy had any effect on spontaneous IL-1 secretion (Stock et al., 1989). Perhaps increased gonadotropin peptide levels in these subjects contributed to these contrary results. Alternatively, assay methods (bioassays vs immunoassays), cell separation protocols (adherent cells vs mixed mononuclear cells) or culture additives such as fetal calf serum (which can contain steroids, cytokines, or cytokine inhibitors) and phenol red (which has estrogenic activity) may be involved. Plasma IL-l bioactivity was low or undetectable in blood samples collected from men and from women during the follicular phase, whereas IL-1 bioactivity was 4-fold higher in luteal phase plasma (Cannon & Dinarello, 1985). Likewise, spontaneous secretion of IL-1 bioactivity by isolated blood monocytes was 10-fold higher in the luteal phase, compared to follicular phase (Polan et al., 1990). More recently, it has been realized that the biological activity of IL-1 depends upon the balance of IL-1 agonists (IL-I~ and IL-lfl) with IL-1 receptor antagonist (IL-lra). IL-lra binds to the same receptors as IL-I~ and IL-lfl, but does not induce a biological response by the target cell (competitive inhibition) (Dinarello, 1991). In absolute terms, the secretion of both IL-1 agonists and antagonist is 2- to 5-fold higher in the follicular phase, but the agonist/antagonist ratio is approximately 45% higher in the luteal phase (Lynch et al., 1994). IL-6 production by human blood cells did not

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J.G. Cannon and B. A. St. Pierre

appear to vary with the menstrual cycle (Leslie & Dubey, 1994), but T N F expression was observed in human endometrial mucosa during the luteal, but not the follicular phase (Philippeaux & Piguet, 1993). During human pregnancy maternal serum IL-1, IL-lra and IL-6 levels increase progressively (Austgulen et al., 1994). Studies with mice indicate that pregnancy may predispose a host defense response toward the Th2 end of the spectrum, rather than a Thl response that may be cytotoxic to the fetus (Krishnan et al., 1996). Human chorionic gonadotropin (hCG) has also been shown to induce IL-1 production in several tissue systems. Secretion of IL-I/~, as well as T N F and IL-6 protein by human blood mononuclear cells was increased in a dose-dependent manner by hCG (Schafer et al., 1992). In other in vitro experiments, hCG induced IL-lfl m R N A in rat ovarian thecainterstitial tissue (Hurwitz et al., 1991 a). In vivo administration of hCG to male rats induced IL-1/~ m R N A in Leydig cells (Lin et al., 1993). IL-1 regulates gonadal and adrenal hormone secretion As the results immediately preceding indicate, IL-1 and other cytokines are actually produced in reproductive tissue. Moreover, IL-1 affects reproductive tissue function by direct action on gonadal cells as well as indirect influences via the hypothalamic-pituitarygonadal axis (shown schematically in Figure 3). Intracerebroventricular (icv) administration of IL-I/?, T N F and IL-6 have all been tested for their ability to inhibit plasma LH levels in castrated male rats (Rivier & Vale, 1990). Whereas 40ng of IL-I/? reduced plasma LH concentrations by 80%, 6-fold higher doses of T N F were only half as effective, and IL-6 had no effect. Furthermore, IL-1/? blocked the LH surge and ovulation in female rats

u_

(Adrenal

es I

Figure 3, Schematicrepresentationof the interactions between the immune system, endocrinesystemand repro-

ductive tissue. Although other inhibitory relationships may exist in this network, two of the major inhibitory pathways are indicated by X's through the arrowheads. Abbreviationsare definedin the footnote on p. 99.

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(Rivier & Vale, 1990). The inhibition was relatively specific for LH, since plasma FSH concentrations were reduced only ~ 28% at the 40 ng dose of IL-1/3. In other studies, ILl/3 inhibited FSH-induced expression of LH receptors on ovarian granulosa cells by up to 60% (Gottschall et al., 1987) and reduced progesterone secretion by 40% (Gottschall et al., 1987; Fukuoka et al., 1989). IL-I/3 also inhibited ovarian theca cell synthesis of androgens by 75% (Hurwitz et al., 1991b); these androgens are precursors used by adjacent granulosa cells for estrogen synthesis. Negative-feedback control of 1L-1 synthesis (and synthesis of other cytokines) is accomplished through the hypothalamic-pituitary-adrenal axis (Besedovsky et al., 1986). IL-I stimulates hypothalamic release of corticotrophin-releasing factor (CRF) (Sapolsky et al., 1987), resulting in adrenocorticotrophic hormone (ACTH) secretion and subsequent release of cortisol (in humans) or corticosterone (in rodents) into the circulation. There is also evidence that IL-I can induce corticosterone secretion through a direct action on the adrenal cortex (Andreis et al., 1991). These corticosteroids, in turn, down-regulate cytokine production in particular (Snyder & Unanue, 1982), and immune function in general (Munck & Guyre, 1991). In adult rats, intravenous injection of IL-1/3 induced ~ 70% higher plasma levels of ACTH and corticosterone in females than males (Rivier, 1994). Gonadectomy negated the sex differences in ACTH levels, however the sex differences in plasma corticosterone persisted with both sexes secreting 2- to 3-fold more corticosterone than intact, sex-matched controls. Chronic fatigue syndrome CFS is a condition of severe, prolonged fatigue combined with other abnormalities such as disruptions in concentration, memory or sleep, and is often associated with musculoskeletal pain (Fukuda et al., 1994). At present CFS has no defined etiology or effective treatment, and differentiating CFS from primary anxiety or depressive disorders is difficult. Over 70% of patients diagnosed with CFS are women (Bates et al., 1994), some of whom experience a worsening of symptoms in the premenstrual period. Is it possible that some of the gender-related differences in immunoreactivity previously discussed may predispose women to CFS? A large and growing number of immunological studies of CFS have been published, and the reader is directed to recent, extensive reviews (Buchwald & Komaroff, 1991; Strober, 1994) for a full account and for primary citations. In brief, some of the T cell abnormalities associated with CFS include reduced proliferation, impaired cytotoxic function and diminished production of IL-2 and IFNT. Recent work suggests that CFS patients may have relatively fewer naive T cells and their memory T cells express characteristics of chronic activation. B cell function measured in vitro has usually been normal, however there have been reports that the relative proportions of immunoglobulin classes and subclasses may be different in CFS patients. Furthermore, a greater incidence of autoantibodies has been detected in CFS patients. The fatigue, low-grade fevers and myagias experienced by CFS patients are similar to the responses observed in other subjects receiving infusion of inflammatory cytokines such as IL-1 and TNF. This realization has led to the hypothesis that dysregulated cytokine

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production may be a mechanism underlying certain aspects of the syndrome. For example, these cytokines mediate fever and induce prostaglandins that potentiate pain (Dinarello, 1991), and they have pervasive effects on energy metabolism (Lang, 1995). TNF influences skeletal muscle membrane potential and rates of proteolysis (Tracey et al., 1986). IL-1 depresses exploratory behavior in rodents (Goujon et al., 1995), increases slow-wave sleep (Kapas et al., 1995), and as described earlier, is a potent activator of the HPA axis. It has been hypothesized that excess production of ACTH and/or CRF may cause depression (Gold et al., 1988). In one study, plasma ACTH levels in CFS patients did correlate with fatigue and depression, however plasma cortisol levels were not elevated, nor were CRF levels in cerebrospinal fluid (Demitrack et al., 1991). In vitro studies have indicated that I L1/~ depresses calcium currents in neurons of the hippocampus (Plata-Salaman & FFrenchMullen, 1992), a structure implicated in glucocorticoid-associated affective disorders (Seckl & Olsson, 1995). Since secretion of IL-1 agonists and antagonists is up to 10-fold higher in women, any defects in the regulation of this cytokine system might result in more prominent manifestations of disease in women than in men. Overexpression of IL-6 in transgenic mice results in hippocampal neurodegeneration (Steffensen et al., 1994), Studies of gender differences in IL-6 production have not been reported, although one study has indicated that no menstrual cycle-related variations in IL-6 production exists (Leslie & Dubey, 1994). Other cytokines, including T G F b have been implicated in neurotoxicity (Chao et al., 1992) that could contribute to diseases of the central nervous system. There is considerable dispute regarding which, if any, cytokines circulate at abnormal levels or are produced at abnormal rates in CFS patients (see Strober, 1994). One reason for these conflicts relates to the use of numerous commercial immunoassay kits that have not been validated for biological samples such as plasma or serum (Whiteside, 1994) and have not been standardized to international reference preparations of cytokines (Bienvenu et al., 1993). Another reason may relate to the immunological differences between men and women. More consensus may emerge if gender and menstrual cycle status were taken into account, not only in cytokine measurement, but all immunological testing. Conclusion Clinical observations that females exhibit enhanced immunoreactivity compared to males suggest female hormones, such as estrogen and progesterone, modulate immune mechanisms. Experimental studies indicate that these gender-specific hormones do have an effect on various immune cells and their function. This effect may be generally characterized as stimulatory: leukocyte concentrations are increased; phagocytic activity and cytotoxicity are enhanced; IL-1 and prostaglandin release are stimulated. In some cases, this immunostimulatory effect by female hormones may be beneficial for host defense. However, the activation of some immune mechanisms by these gonadal hormones in the wrong circumstances may lead to the development of disease. Whether such hormonal modulation is an underlying explanation for the ~ 3:1 preponderance of women in CFS is a question requiring further research. Acknowledqement--The research of the authors is supported by NIH grants AI33414,AR39595 (to JGC) and

NR07097 (to BAS).

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