Local cytokine levels associated with delayed-type hypersensitivity responses: modulation by gender, ovariectomy, and estrogen replacement

Abstract

It is well established that females mount stronger immune responses than males, but only very little is understood about the underlying mechanisms. We have analyzed local cytokine differences among intact females, those that had been ovariectomized (OVX), those receiving estrogen replacement after OVX, and males, both before and after production of delayed-type hypersensitivity (DTH) responses. We report confirmation of a much larger DTH response in females versus males. However, OVX resulted in an even larger response, while estrogen replacement resulted in a smaller response when compared with intact females. In animals exposed for the first time to an antigen (without a DTH response), OVX increased interleukin-6 (IL-6) and estrogen replacement after OVX suppressed IL-6. Of the cytokines that differed between males and females exposed for the first time to an antigen, only IL-6 was higher in females versus males when exposure to antigen occurred for the second time (when the DTH response occurs). Analysis of cytokines with OVX and estrogen replacement after a second exposure to antigen showed that IL-6 did not significantly change. Levels of IL-4; Regulated upon Activation, Normal T-cell Expressed; and Secreted; and thrombopoietin, however, correlated with the DTH response, suggesting direct or indirect positive regulation by estrogen. These results suggest an important role for both IL-6 and IL-4 in determining the degree of DTH response, with IL-6 (which appears negatively regulated by estrogen) increasing and IL-4 (which appears positively regulated by estrogen) decreasing the response. The results further suggest that IL-6 may play a role in predisposing to a larger DTH response, while IL-4 levels seem more important during an active response.

Trans-Epithelial Immune Cell Transfer during Suckling Modulates Delayed-Type Hypersensitivity in Recipients as a Function of Gender

“…This is in contrast to older animals (12 weeks) where we [29] and others [reviewed in 30] have demonstrated a more robust response in females. Nursing by a sensitized dam did not just accelerate this gender difference because nursing also resulted in suppression of the response in the males.…”

Selective estrogen receptor modulators in T cell development and T cell dependent inflammation

“…The mechanism for the suppressive effects of E2 on DTH is not clear, but E2 is not believed to directly affect T cells in DTH as female severe combined immunodeficient (SCID) mice reconstituted with thymocytes from E2-treated mice did not show a decrease in the DTH response (Taube et al, 1998). Instead, the E2-mediated inhibition of DTH is believed to involve a decrease in the antigen presentation to T cells and an alteration of the cytokine pattern (Salem et al, 2000;Ma et al, 2007). Similarly, E2 treatment reduces the ability of splenic DCs to present antigen to T cells and to produce proinflammatory cytokines in other inflammatory models (Liu et al, 2002).…”

Role of Prolactin in Promotion of Immune Cell Migration into the Mammary Gland

“…More recently, evidence that some milk immune cells can pass from the milk across the wall of the gastrointestinal tract and into the neonate has accumulated. This occurs in a variety of species, including rats [18,19], sheep [18,20], pigs [21], baboons [22], and mice [23,24,25]. While many of these studies used concentrated cells and delivery by gavage, others have demonstrated the movement of cells into the neonate under entirely physiological conditions, and gone on to demonstrate that these cells affected subsequent immune responses in the recipients when adult [25,26].…”