Estrogen mediates the sex difference in post-burn immunosuppression

Gregory, Meredith S.; Duffner, LA; Faunce, Douglas E.; Kovacs, Elizabeth J.

doi:10.1677/joe.0.1640129

Cited by 87 publications

(51 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1,4 However, the possibility that drastic changes in cytokine levels in the early stages after a BMT could be solely induced by hypogonadism appears to be low. Although there is a large body of evidence suggesting that the decline in the ovarian function is associated with the spontaneous increase in the proinflammatory cytokines, efforts to demonstrate that the cytokine increases are related to the estrogen deficiency in tissue samples in vivo 13,14 or in circulation [15][16][17][18] have been less successful. Increases in the IL-6 and TNF-a levels with an estrogen deficiency are subtle compared with the increases observed as a host reaction to an infection or a major tissue injury.…”

Section: Discussionmentioning

confidence: 99%

Impact of circulating bone-resorbing cytokines on the subsequent bone loss following bone marrow transplantation

Lee

Baek

Rhee

et al. 2004

Bone Marrow Transplant

View full text Add to dashboard Cite

Summary:Cytokines including IL-6 and TNF-a play an important role in the pathogenesis of postmenopausal osteoporosis. However, the relationship between changes in the cytokine levels and subsequent bone loss in patients undergoing a bone marrow transplantation (BMT) is unclear. A total of 46 patients undergoing an allogeneic BMT were prospectively investigated. The bone turnover markers and the serum cytokines were measured before BMT and serially after BMT. Bone mineral density (BMD) was measured before and 1 year after BMT. At 1 year after BMT, the lumbar spine BMD had decreased by 4.8%, and the total proximal femoral BMD had decreased by 12.3%. The serum IL-6 and TNF-a levels increased until 2 and 3 weeks after BMT, respectively. The lumbar BMD was significantly decreased as the serum IL-6 and TNF-a levels increased by post-BMT 3 weeks. The lumbar BMD decreased significantly as the cumulative prednisolone and cyclosporine dose increased. Patients with GVHD Xgrade II had higher lumbar bone loss than patients with GVHD ograde I. In conclusion, immunosuppressants, GVHD occurrence and increase in bone-resorbing cytokines in the early post-BMT period were associated with later bone loss after BMT. Further studies are needed to elucidate the precise mechanism. Bone marrow transplantation (BMT) is an established method for treating various hematological diseases. As the number of long-term survivors increased due to the improved prognosis after BMT, the number of endocrine complications has also increased. Endocrine complications brought about after a BMT include hypogonadism, thyroid dysfunction, hypopituitarism, diabetes and osteoporosis. A significant bone loss occurs during the first year after a BMT with up to a 5-10% decrease in the bone mineral density (BMD) in the lumbar spine and proximal femur. The post-BMT bone loss is mainly related to the immunosuppressants and the gonadal dysfunctions secondary to myeloablative therapy and/or total body irradiation (TBI). [1][2][3][4][5] The rapid impairment in bone formation and the increase in bone resorption, as mirrored by the biochemical markers, might play a role in bone loss, particularly during the early post-BMT period. 1 The pathogenic role of the cytokines is well known in the development of postmenopausal osteoporosis and other forms of secondary osteoporosis. Interleukin-6 (IL-6), interleukin-1 (IL-1) and tumor necrosis factor-a (TNF-a) are known to increase bone resorption by stimulating osteoclasts. 6 However, there are few reports on the relationship between changes in the bone metabolism and cytokine levels after a BMT. 7,8 In particular, there is no report on the effects of the drastically changing cytokine levels in the early post-BMT period on the long-term changes in the BMD after a BMT. It was previously reported that the bone marrow plasma IL-6 level, which reflects the real changes in the bone marrow microenvironment, was significantly related to the serum bone resorption markers after a BMT. 8 This study measured the serum IL-6, TNF-a and bone ...

show abstract

Section: Discussionmentioning

confidence: 99%

Impact of circulating bone-resorbing cytokines on the subsequent bone loss following bone marrow transplantation

Lee

Baek

Rhee

et al. 2004

Bone Marrow Transplant

View full text Add to dashboard Cite

show abstract

“…Flutamide did not increase circulating levels of testosterone [33], but it did increase estrogen levels (KAN Messingham, MA Emanuele, and EJ Kovacs unpublished observations) as well as estrogen receptor expression following burn [96]. Additionally, as mentioned earlier, burn causes a rise in estrogen levels in female mice to those resembling pregnancy (immunosuppressive) where levels of estrogen in burned male mice reach low levels such as that of sham females (immunostimulatory) [75]. These data suggest that specific levels of gonadal steroids are a key component to a positive outcome following injury.…”

Section: Burn and Co-morbidity Factorsmentioning

confidence: 98%

“…Following burn, there is an increase in circulating estrogen levels in mice, reaching levels of the hormone capable of attenuating DTH responses and Concavalin-A (Con-A)-stimulated splenocyte proliferation [75]. At late time points following burn injury (10 days), suppression of the immune response in females was observed.…”

Section: Adaptive Immune Response Following Injurymentioning

confidence: 99%

“…Similarly, intact male mice given burn and estrogen had significantly decreased DTH responses as did OVX female mice given estrogen at 10 days post burn. In contrast, treatment with an estrogen antagonist (17-α estradiol) restored this memory response, as well as IL-6 production, in intact female mice given burn injury to that of sham levels [75]. Cellular proliferation following stimulation with Con-A was measured ex vivo in mice subjected to a 15% total body surface area (TBSA) burn injury.…”

Section: Adaptive Immune Response Following Injurymentioning

confidence: 99%

See 1 more Smart Citation

Sex differences and estrogen modulation of the cellular immune response after injury

Bird¹,

Karavitis²,

Kovacs³

2008

Cellular Immunology

View full text Add to dashboard Cite

Cell-mediated immunity is extremely important for resolution of infection and for proper healing from injury. However, the cellular immune response is dysregulated following injuries such as burn and hemorrhage. Sex hormones are known to regulate immunity, and a well-documented dichotomy exists in the immune response to injury between the sexes. This disparity is caused by differences in immune cell activation, infiltration, and cytokine production during and after injury. Estrogen and testosterone can positively or negatively regulate the cellular immune response either by aiding in resolution or by compounding the morbidity and mortality. It is apparent that the hormonal dysregulation is dependent not only on the type of injury sustained but also the amount of circulating hormones. Therefore, it may be possible to design sex-specific therapies to improve immunological function and patient outcome.

show abstract

“…Male BALB/c mice 10 weeks of age (Charles River Laboratories, Portage, MI, USA) were subjected to dorsal scald injury as previously described (Gregory et al 2000a). Briefly, mice were anesthetized (40 mg/kg sodium pentobarbital in 0·9% normal saline, i.p.…”

Section: Induction Of Thermal Injurymentioning

confidence: 99%

Testosterone receptor blockade restores cellular immunity in male mice after burn injury

Messingham¹,

Shirazi²,

Duffner³

et al. 2001

Journal of Endocrinology

Self Cite

View full text Add to dashboard Cite

Males are known to have increased risk for septic complications after traumatic injury, which appears to be mediated by the inhibitory effects of testosterone on immune function. The role of testosterone in immunity after burn injury, however, remains unclear. Herein, we examined the effects of a testosterone receptor antagonist, flutamide, on delayed type hypersensitivity response (DTH), splenocyte proliferation, interleukin (IL)-2 secretion, and IL-2 receptor (IL-2R) expression in male BALB/c mice subjected to a 15% total body surface area burn or sham injury. Burn-or sham-injured mice were given flutamide s.c. at 30 min and 24 h after injury. At 48 h, burn injury caused a 48% (P<0·001) decrease in DTH response; however, mice that received flutamide treatment did not demonstrate significant suppression of DTH. Likewise, splenocyte proliferation and IL-2 production were depressed in burned animals in comparison with sham-injured controls, and flutamide treatment resulted in a partial restoration of these responses. In vitro studies indicated that splenocytes from sham-and burninjured mice were equally sensitive to the suppressive effects of 5 -dihydrotestosterone in regard to proliferation and IL-2 production. Further evaluation revealed a decrease in IL-2R expression on splenocytes from burned mice and a partial restoration of this expression with flutamide treatment. Thus blocking testosterone receptor activation improves the cellular immunity in thermally injured mice, possibly through restoration of IL-2 production and IL-2R expression. It remains to be determined whether the effects of testosterone in this injury model are direct or indirect.

show abstract

Estrogen mediates the sex difference in post-burn immunosuppression

Cited by 87 publications

References 53 publications

Impact of circulating bone-resorbing cytokines on the subsequent bone loss following bone marrow transplantation

Impact of circulating bone-resorbing cytokines on the subsequent bone loss following bone marrow transplantation

Sex differences and estrogen modulation of the cellular immune response after injury

Testosterone receptor blockade restores cellular immunity in male mice after burn injury

Contact Info

Product

Resources

About