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Laboratory of Immunology Division of Therapeutic Proteins Center for Drug Evaluation and Review Food and Drug Administration Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: Dr. Daniela Verthelyi, Laboratory of Immunology, Division of Therapeutic Proteins, Center for Drug Evaluation and Review, Food and Drug Administration, Building 29A, Room 3B19, 8800 Rockville Pike, Bethesda, Maryland 20892. E-mail: verthelyi{at}cber.fda.gov.
Identifying and eliminating infectious pathogens is a critical function of the immune system. Accomplishing this goal requires the synergistic interaction of innate and adaptive immunity. The innate immune system is activated by receptors that recognize conserved pathogen associated molecular patterns (PAMPs) through a limited set of germline encoded receptors such as the Toll-like receptor (TLR) family. Their response limits the spread of invading pathogens and facilitates the induction of an adaptive response, which in turn controls pathogens through affinity-matured B cells that generate high-affinity antigen-specific antibodies and pathogen-specific T cells that selectively lyse infected targets. When successful, these systems provide a tightly regulated response that clears the offending pathogen without eliciting extensive tissue damage or autoimmunity.
When it comes to the innate and adaptive arms of the immune system, however, men and women are not equal. Women are more resistant to infection, mount stronger humoral immune responses to vaccines, and reject allografts and tumors more successfully than males (reviewed in Refs.1 and 2). Several cells of the immune system including dendritic cells (DCs), natural killer cells, macrophages, and lymphocytes express estrogen receptors, suggesting that this hormone modulates their function. Indeed, relative increases in estrogen levels are associated with polyclonal B cell activation; enhanced antigen presentation by DCs; and increased IL-6, IL-10, and interferon (IFN)
production, which determine a shift in the cytokine milieu. Unfortunately, those differences are also thought to play an important role in the higher susceptibility of women to autoimmune diseases (1, 2, 3).
In this issue of Endocrinology, Karpuzoglu et al. (4) provide evidence that differences in estrogen levels between male and female mice impact the expression of inducible nitric oxide synthase (iNOS), an enzyme that catalyzes the conversion of L-arginine to citrulline and nitric oxide (NO). Macrophages are the dominant source of iNOS in vivo, although DCs, mast cells, and other phagocytic cells such as monocytes, microglia, Kupffer cells, eosinophils, and neutrophils (expression on lymphocytes remains controversial) also express it (5). Induction of high levels of iNOS often requires the synergistic effect of type I and II IFNs, plus the stimulation of antigen presenting cells (APC) through the TLRs by PAMPS such as bacterial DNA (recognized by TLR-9) or lipopolysaccharide (recognized by TLR-4) (5, 6). The expression of iNOS leads to the production of NO, a highly diffusible uncharged gas that increases the lytic function of phagocytes and modulates the production of proinflammatory cytokines such as TNF-
and IL-6. The resulting NO increases the cytostatic and cytotoxic activity of DCs, monocytes, and macrophages against viruses, bacteria, protozoa, helminthes, and tumor cells. The key contribution of iNOS to host protection was demonstrated in studies in iNOS–/– mice. When challenged with either Leishmania major or Listeria monocytogenes, the absence of iNOS prevented host control of infection (6, 7). It is important to note that NO, depending on its concentration and tissue localization, can have both pro- and antiinflammatory effects on the host. Examples of this dual effect are the inflammation followed by cartilage and bone destruction associated with elevated NO levels in the joints of rheumatoid arthritis patients and the antiinflammatory effects of NO that were observed in models of ischemia, in which low levels of NO limit neutrophil infiltration and tissue damage and improve area perfusion (8, 9). Adding complexity, NO can partner with a variety of compounds (DNA, proteins, thiols, prosthetic groups, and reactive oxygen intermediates) that modulate its effects (5, 9).
A number of recent studies show that estrogen can differentially impact the expression of iNOS depending upon the concentration of hormone and the tissue being studied. Thus, in the brain, estrogens reduce iNOS expression and NO concentrations in microglia, creating an antiinflammatory milieu that improves outcome after ischemic stroke (10, 11, 12). In contrast, in the rat intestinal wall ischemic injury model, Xiao et al. (13) report that estrogen-associated increase in iNOS expression was coupled with reduced histological scores.
Previous reports examining the role of estrogen in macrophage production of iNOS indicate that low concentrations of hormone (10–12 to 10–8 M) induce resting macrophages to increase their expression of iNOS (14). However, the iNOS response of macrophages to IFN plus lipopolysaccharide (signaling through TLR-4) appears to be reduced when cells are exposed to higher estrogen concentrations (>10–10 M) (15). The range of estrogen activity that is stimulatory is consistent with data from our lab showing that human monocytes stimulated with a TLR9 agonist produce higher amounts of IFN and CXCL10 when cultured in the presence of estrogen concentrations of 10–12 to 10–8 M, but both TLR-induced responses were significantly reduced when higher estrogen concentrations (10–7 to 10–5 M) are used (Puig, M., and D. Verthelyi, manuscript in preparation). Together these data suggest that estrogen has a direct effect on the activation of monocytes and macrophages by TLR ligands.
Karpuzoglu et al. (4) present an alternative mechanism to explain the effects of estrogen on the regulation of iNOS by APC. Because purified cell populations were not evaluated, we can only presume that the work of Karpuzoglu et al. primarily involved iNOS production by DC, monocytes, and macrophages. Their studies demonstrate that T cells from orchiectomized male mice treated with slow-release implants yielding physiological estrogen serum levels (16) produce high levels of IFN in response to signals that fail to induce IFN from T cells from placebo-treated orchiectomized animals. Their findings indicate that their T cells are likely activated through the classical T cell receptor plus a costimulatory molecule pathway and respond by secreting high levels of IFN, which mediates an increase in iNOS expression by the surrounding APC. Although Karpuzoglu et al. fail to establish whether the iNOS expression by APC is enhanced by the exposure of the APC to estrogens, it is likely that such an increase in iNOS would improve the APC’s ability to lyse microbes (improving host survival after infectious challenge).
An interesting observation made by Karpuzoglu et al. is that the exposure to estrogen rendered T cells susceptible to respond to suboptimal levels of anti-CD3 or Concanavalin A. These findings suggest a potential route for initiating an immune response to irrelevant or "self" antigens that would otherwise be ignored. Such a pathway could contribute to the increased susceptibility of females to autoimmune diseases.
Autoimmune diseases, such as type I diabetes mellitus, lupus erythematosus, myocarditis, rheumatoid arthritis, and multiple sclerosis, are significantly more common in women than men, but also tend to manifest or flare up after infections. As stated above, TLR receptors have been defined by their role in the recognition and control of microbes. However, a growing number of studies suggest that their ability to trigger APC to 1) increase antigen presentation (by up-regulating major histocompatibility complex and costimulatory molecules) (17), 2) secrete proinflammatory cytokines (18), 3) promote a T helper 1 type of adaptive immune response (19), and 4) block the suppressive effect of regulatory T cells that control naïve CD4 T cell activation (20) may play a critical role in the development of some autoimmune diseases (21, 22, 23). Of note, several recent studies show that, in culture, estrogen further enhances TLR-mediated DC maturation and augments the production of proinflammatory cytokines and chemokines in response to PAMPs (24, 25).
Considering the findings of Karpuzoglu et al. in this context, one could envision a model (Fig. 1
) in which TLR-mediated activation in a permissive hormonal milieu could increase the susceptibility of T cells to respond to antigens that would otherwise be ignored (acting directly on the T cells and/or enhancing the ability of APCs to activate T cells). The resulting increase in IFN production would then synergize with the TLR ligands to stimulate the expression of high levels of iNOS-dependent NO and cyclooxygenase-2, as well as proinflammatory cytokines and chemokines. This could create a positive feedback loop that would amplify the inflammatory response and, given the appropriate genetic background, lead to autoimmune disease. The work of Karpuzoglu et al. (5) opens up new lines of investigation that will lead toward the development of rational strategies for treating patients with autoimmune and inflammatory diseases.
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Footnotes |
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The assertions herein are the personal ones from the author and are not to be construed as official or as reflecting the views of the Food and Drug Administration.
The author has no conflicts of interest to report.
Abbreviations: APC, Antigen presenting cells; DC, dendritic cell; IFN, interferon; iNOS, inducible nitric oxide (NO) synthase; PAMP, pathogen associated molecular patterns; TLR, Toll-like receptor.
Received November 18, 2005.
Accepted for publication November 21, 2005.
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, IL-2 and IL-4 gene expression and protein synthesis in spleen and thymus of normal C57BL/6 mice. Cytokine 14:208–217[CrossRef][Medline]. Endocrinology 147:662–671
B activation induced by transient cerebral ischemia. Brain Res 1008:147–154[CrossRef][Medline]-dihydrotestosterone, augments antibodies to double stranded deoxyribonucleic acid in nonautoimmune C57BL/6J mice. Endocrinology 135:2615–2622[Abstract]This article has been cited by other articles:
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  R. Raju and I. H. Chaudry Sex Steroids/Receptor Antagonist: Their Use as Adjuncts After Trauma-Hemorrhage for Improving Immune/Cardiovascular Responses and for Decreasing Mortality from Subsequent Sepsis Anesth. Analg., July 1, 2008; 107(1): 159 - 166. [Abstract] [Full Text] [PDF]
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 M. C. Siracusa, M. G. Overstreet, F. Housseau, A. L. Scott, and S. L. Klein 17{beta}-Estradiol Alters the Activity of Conventional and IFN-Producing Killer Dendritic Cells J. Immunol., February 1, 2008; 180(3): 1423 - 1431. [Abstract] [Full Text] [PDF]
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