Elsevier

Surgery

Volume 138, Issue 2, August 2005, Pages 275-282
Surgery

Society of University Surgeons
The influence of gender on human innate immunity

https://doi.org/10.1016/j.surg.2005.03.020Get rights and content

Background

Several experimental, clinical, and epidemiologic studies indicate a better prognosis in women after an infectious challenge. The monocyte/macrophage, as coordinators of the innate immune response to sepsis, secrete plasma inflammatory cytokines. Elevated plasma cytokine levels are inversely correlated with outcome. In addition, single–nucleotide polymorphisms related to these cytokine genes and in genes important for lipopolysaccharide (LPS) detection, particularly toll-like receptor-4, have been associated with variations in clinical outcome. We hypothesize that the gender differences in clinical outcome are due to measurable differences in cytokine responses and intracellular signaling, and these differences are independent of polymorphism carrier status.

Methods

Venous blood samples from healthy subjects (56 men, 23 women) were incubated with LPS, and supernatant cytokine levels were determined by enzyme-linked immunosorbent assay. In a randomly chosen subgroup, (8 men, 4 women), peripheral blood mononuclear cells were isolated, and LPS-mediated intracellular mitogen-activated protein kinase (MAPK) phosphorylation was assayed via Western blot analysis. Each subject was screened for the following SNPs: tumor necrosis factor α (TNF-α) -308G/A, interleukin (IL)-6 -174G/C, IL-1β -31C/T, and toll-like receptor-4 (TLR4) +896A/G.

Results

Women produced significantly less LPS-induced TNF-α and IL-1β but not IL-6. When the analysis was adjusted for the presence of each polymorphism, the differences in TNF-α and IL-1β accumulation persisted. Female gender was associated with lower MAPK phosphorylation at each LPS concentration but was not statistically significant.

Conclusions

Gender-specific differences in LPS-induced TNF-α and IL-1β were observed, possibly attributed to alterations in MAPK phosphorylation. Furthermore, studies investigating the influence of genomic variation on the innate immune response should address potential gender-related differences.

Section snippets

Material and methods

All studies were approved by the University of Washington Institutional Review Board, and all subjects provided written informed consent.

Demographic and genomic features

This study included 56 male and 23 female healthy subjects. Baseline characteristics of each group including age, ethnicity, and medications are shown in Table II. Age was similar among the 2 genders. More women were taking nonsteroidal anti-inflammatory drugs other than aspirin within 72 hours of their blood draw.

Endotoxin-mediated inflammatory cytokine production is influenced by gender

Whole blood LPS–induced cytokine responses from all 79 healthy subjects were determined. Both male and female groups demonstrated substantial within-group variation in the

Discussion

The clinical and experimental observation that gender differences exist in the susceptibility to and outcomes from infection has been a subject of intense investigation. A preponderance of men among septic surgical patients was reported first by McGowan et al37 in 1975. In a large review of discharge data from approximately 750 million hospitalizations in the United States over 20 years, Martin et al7 found that the annual incidence of sepsis was almost 30% higher among men than women (mean

Conclusion

Gender-specific differences in LPS-induced inflammatory cytokine production exist and may explain differences in clinical outcome. Furthermore, these differences persist despite adjustment for relevant polymorphisms, suggesting gender is an important determinant of the innate immune response.

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    Presented at the 66th Annual Meeting of the Society of University Surgeons, Nashville, Tennessee, February 9-12, 2005.

    Supported by grant T32 GM 07037.

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