Cytokines, leptin, and stress-induced thymic atrophy - PubMed (original) (raw)

Review

Cytokines, leptin, and stress-induced thymic atrophy

Amanda L Gruver et al. J Leukoc Biol. 2008 Oct.

Abstract

Thymopoiesis is essential for development and maintenance of a robust and healthy immune system. Acute thymic atrophy is a complication of many infections, environmental stressors, clinical preparative regimens, and cancer treatments used today. This undesirable sequela can decrease host ability to reconstitute the peripheral T cell repertoire and respond to new antigens. Currently, there are no treatments available to protect against acute thymic atrophy or accelerate recovery, thus leaving the immune system compromised during acute stress events. Several useful murine models are available for mechanistic studies of acute thymic atrophy, including a sepsis model of endotoxin-induced thymic involution. We have identified the IL-6 cytokine gene family members (i.e., leukemia inhibitory factor, IL-6, and oncostatin M) as thymosuppressive agents by the observation that they can acutely involute the thymus when injected into a young, healthy mouse. We have gone on to explore the role of thymosuppressive cytokines and specifically defined a corticosteroid-dependent mechanism of action for the leukemia inhibitory factor in acute thymic atrophy. We also have identified leptin as a novel, thymostimulatory agent that can protect against endotoxin-induced acute thymic atrophy. This review will highlight mechanisms of stress-induced thymic involution and focus on thymosuppressive agents involved in atrophy induction and thymostimulatory agents that may be exploited for therapeutic use.

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Figures

Fig. 1.

Model of stress-induced thymic atrophy and thymosuppressive and thymostimulatory mediators. LIF, Leukemia inhibitory factor; OSM, oncostatin M; KGF, keratinocyte growth factor; hGH, human growth hormone; TSLP, thymic stromal lymphopoietin.

Fig. 2.

A single injection of LPS-induced acute thymic atrophy with subsequent recovery. BALB/c mice were treated with saline or LPS (100 μg i.p.) on Day 0, and mice were killed on Days 1, 3, 7, 11, 15, 21, and 28 to monitor thymopoiesis (_n_=3). Mean thymus weight (A), absolute number of CD4/CD8 DP thymocytes (B), and molecules of mTREC per milligram of thymus tissue (C) ±

sem

were determined at each harvest time. *, P ≤ 0.05, compared with saline-treated controls [37].

Fig. 3.

Neutralization of gp130 protected against loss of mTREC/mg thymus in LPS-treated mice. BALB/c mice were treated with LPS (100 μg i.p.) or LPS + anti-gp130 polyclonal-neutralizing antibodies on Day 0, and mice were killed on Day 3 (_n_=5). *, P ≤ 0.05, compared with LPS-treated controls.

Fig. 4.

Leptin protected against LPS-induced thymic atrophy and modulated the systemic response to LPS. Female BALB/c mice were simultaneously administered (i.p.) saline or leptin (1 μg/g body weight) and challenged with saline or E. coli LPS (100 μg/mouse). Mice were killed on Days 1, 7, and 14 to monitor thymopoiesis (_n_=5). Mean thymus weight Day 7 (A). Serum corticosterone levels were determined 4 h post-treatment (B). Serum IL-1β cytokine levels (C) and serum IL-12p70 cytokine levels (D). *, P ≤ 0.05, compared with LPS-treated controls [37].

References

1. Steinmann G G. Changes in the human thymus during aging. Curr Top Pathol. 1986;75:43–88. - PubMed
1. Steinmann G G, Klaus B, Muller-Hermelink H K. The involution of the ageing human thymic epithelium is independent of puberty. A morphometric study. Scand J Immunol. 1985;22:563–575. - PubMed
1. Haynes B F, Denning S M, Singer K H, Kurtzberg J. Ontogeny of T-cell precursors: a model for the initial stages of human T-cell development. Immunol Today. 1989;10:87–91. - PubMed
1. Haynes B F, Hale L P. The human thymus. A chimeric organ comprised of central and peripheral lymphoid components. Immunol Res. 1998;18:175–192. - PubMed
1. Kaye J. Regulation of T cell development in the thymus. Immunol Res. 2000;21:71–81. - PubMed

Cytokines, leptin, and stress-induced thymic atrophy - PubMed (original) (raw)