# AGING AND TNF-GLUCOCORTICOID INTERACTIONS IN SEPSIS

> **NIH NIH R01** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 1993 · $154,788

## Abstract

Infectious diseases are a major cause of morbidity and mortality in the
elderly population. For example, Gram negative sepsis may exceed 50% in
the aged population. This is due particularly to improved medical
technology that allows individuals to live longer, yet ironically, places
them at increased risk to secondary infection. There is substantial
evidence implicating endotoxin as a major virulence determinant in Gram
negative septicemia. Cytokines, particularly tumor necrosis factor, (TNF),
appear to be major effectors of endotoxic reactions. Glucocorticoid
hormones have been shown to regulate the synthesis of TNF as well as
influence the response of target cells to it. The focus of this proposed
study will be on age associated differences in TNF-glucocorticoid
interaction in sepsis.  Results of preliminary studies revealed that
senescent C57BL/6NNia mice (24 months old) died much earlier than young
(4-6 months old) or mature (12 months old) mice after the induction of
acute peritonitis and sepsis by cecal ligation and puncture (CLP). We
propose that the increased sensitivity of senescent mice to sepsis and
endotoxemia is related to the interaction of glucocorticoid hormones with
tumor necrosis factor. Senescent animals produced 20 to 30-fold more serum
TNF than mature mice when administered E.coli endotoxin. Furthermore, the
usual down-regulation of TNF production by exogenous glucocorticoids was
not observed in endotoxic senescent mice.  WE HYPOTHESIZE THAT DISRUPTED
GLUCOCORTICOID REGULATION OF TNF GENE EXPRESSION MAY UNDERLIE THE
INCREASED SENSITIVITY OF AGED ANIMALS TO SEPSIS. In the proposed study we
will define the role of glucocorticoids in age associated differences in
TNF production by endotoxic mice. We will utilize the glucocorticoid
antagonist, RU486, for in vivo experiments in which the effect of
glucocorticoid receptor blockade on TNF production will be examined.
Peritoneal macrophages will be isolated from young, mature and senescent
mice for in vitro studies of the influence of dexamethasone on TNF
synthesis. A second Aim is to investigate if altered glucocorticoid
regulation of TNF production in aged animals occurs at the TNF gene level.
We will develop and utilize transgenic mice carrying a TNF:CAT gene
construct to study the influence of glucocorticoids in vivo on TNF gene
expression. For in vitro studies, a variety of TNF:CAT gene constructs
will be used to transfect primary peritoneal macrophages to examine the
effect of glucocorticoids, RU486 and actinomycin D on TNF production. Our
long term goal is to understand TNF-glucocorticoid interactions so that
the increased sensitivity of aged mammals to bacterial sepsis can be
reduced through more effective therapeutic intervention.

## Key facts

- **NIH application ID:** 3123443
- **Project number:** 1R01AG011530-01
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **SAM.gov UEI:** HFT7XTHB6563
- **Principal Investigator:** RODERICK E MCCALLUM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $154,788
- **Award type:** 1
- **Project period:** 1993-09-30 → 1997-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3123443

## Citation

> US National Institutes of Health, RePORTER application 3123443, AGING AND TNF-GLUCOCORTICOID INTERACTIONS IN SEPSIS (1R01AG011530-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3123443. Licensed CC0.

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