Laboratory of Experimental Rheumatology and Neuroendocrino-Immunology, Division of Rheumatology, Department of Internal Medicine I, University Hospital, 93042 Regensburg, Germany
Correspondence: Address all correspondence and requests for reprints to: Rainer H. Straub, M.D., Professor of Experimental Medicine, Laboratory of Experimental Rheumatology and Neuroendocrino-Immunology, Department of Internal Medicine I, University Hospital, 93042 Regensburg, Germany. E-mail: rainer.straub{at}klinik.uni-regensburg.de
There is still an unresolved paradox with respect to the immunomodulatingrole of estrogens. On one side, we recognize inhibition of boneresorption and suppression of inflammation in several animalmodels of chronic inflammatory diseases. On the other hand,we realize the immunosupportive role of estrogens in trauma/sepsisand the proinflammatory effects in some chronic autoimmune diseasesin humans. This review examines possible causes for this paradox.
This review delineates how the effects of estrogens are dependenton criteria such as: 1) the immune stimulus (foreign antigensor autoantigens) and subsequent antigen-specific immune responses(e.g., T cell inhibited by estrogens vs. activation of B cell);2) the cell types involved during different phases of the disease;3) the target organ with its specific microenvironment; 4) timingof 17ß-estradiol administration in relation to thedisease course (and the reproductive status of a woman); 5)the concentration of estrogens; 6) the variability in expressionof estrogen receptor and ß depending on the microenvironmentand the cell type; and 7) intracellular metabolism of estrogensleading to important biologically active metabolites with quitedifferent anti- and proinflammatory function. Also mentionedare systemic supersystems such as the hypothalamic-pituitary-adrenalaxis, the sensory nervous system, and the sympathetic nervoussystem and how they are influenced by estrogens.
This review reinforces the concept that estrogens have antiinflammatorybut also proinflammatory roles depending on above-mentionedcriteria. It also explains that a uniform concept as to theaction of estrogens cannot be found for all inflammatory diseasesdue to the enormous variable responses of immune and repairsystems.
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and ß depending on the microenvironment and the cell type; and 7) intracellular metabolism of estrogens leading to important biologically active metabolites with quite different anti- and proinflammatory function. Also mentioned are systemic supersystems such as the hypothalamic-pituitary-adrenal axis, the sensory nervous system, and the sympathetic nervous system and how they are influenced by estrogens. 
