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. 2004 Jul;53(7):965-72.
doi: 10.1136/gut.2003.027136.

Leptin receptor expression on T lymphocytes modulates chronic intestinal inflammation in mice

B Siegmund  1 , J A Sennello, J Jones-Carson, F Gamboni-Robertson, H A Lehr, A Batra, I Fedke, M Zeitz, G Fantuzzi
Affiliations

Leptin receptor expression on T lymphocytes modulates chronic intestinal inflammation in mice

B Siegmund et al. Gut. 2004 Jul.

Abstract

Background: Leptin regulates appetite through the long isoform of its receptor in the hypothalamus. Although leptin regulates immune responses, it is still unknown whether a direct effect of leptin on lymphocytes is required.

Aims: To clarify whether expression of leptin receptors on T lymphocytes modulates intestinal inflammation in mice.

Methods: The model of colitis induced by transfer of CD4(+)CD45RB(high) (RB(high)) cells into scid mice was used. Wild-type (WT) or leptin receptor deficient (db/db) RB(high) cells were transferred into scid mice and development of colitis evaluated.

Results: Leptin receptors were expressed on both RB(high) and RB(low) cells. Intestinal lymphocytes of mice with colitis expressed high leptin levels compared with healthy controls whereas the opposite was true for serum leptin levels. Transfer of RB(high) cells from db/db mice induced delayed disease compared with transfer of WT cells. A high rate of apoptosis in lamina propria lymphocytes and reduced cytokine production were observed early on in scid mice receiving db/db RB(high) cells. These effects were not due to the high levels of glucocorticoids present in db/db mice as administration of corticosterone to WT mice failed to reproduce this phenomenon. High expression of peroxisome proliferator activated receptor gamma was observed in the colon of recipients of db/db compared with WT cells. Freshly isolated db/db RB(high) cells produced low levels of interferon gamma. Despite delayed onset of colitis, as disease progressed differences between mice receiving WT or db/db cells were no longer apparent.

Conclusions: These results suggest that leptin affects the immune response, partly by acting on the long isoform of its receptor expressed on T lymphocytes.

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Figures

Figure 1
Figure 1
Expression of leptin receptor (LEPR-B) on RBhigh and RBlow cells. Western blot analysis for LEPR-B was performed on sorted wild-type (WT) and leptin receptor deficient (db/db) RBhigh and RBlow cells (top panel). The bottom panel indicates equal protein loading, as evaluated by blotting with an antiactin antibody.
Figure 2
Figure 2
Expression of leptin in lamina propria lymphocytes (LPL) and mesenteric lymph node cells (MLN). LPL and MLN were extracted from healthy controls and from diseased scid mice that had received wild-type (WT) RBhigh cells eight weeks earlier. Cells were stained for leptin (red) and analysed by confocal microscopy. Green represents membrane sialoproteins and blue the nucleus.
Figure 3
Figure 3
Delayed disease in scid mice injected with leptin receptor deficient (db/db) RBhigh cells. Scid mice were injected with wild-type (WT) or db/db RBhigh cells. (A) Disease score. (B) Histological scores at weeks 5, 8, and 12. (C) Histology at week 5 and week 12. Representative sections are shown from recipients of WT and db/db cells. Data are mean (SEM) of 20 mice per group. *p<0.05, **p<0.01, ***p<0.001 versus WT.
Figure 4
Figure 4
High rates of apoptosis in lamina propria lymphocytes (LPL) of mice receiving leptin receptor deficient (db/db) RBhigh cells. Scid mice were injected with wild-type (WT) or db/db RBhigh cells. Controls were untreated Balb/c mice. At weeks 5 and 12, a group of three mice per experimental group was sacrificed for valuation of LPL apoptosis by flow cytometry. Results shown are representative of two independent experiments, each with three mice per group.
Figure 5
Figure 5
Altered cytokine production in colon cultures of mice receiving leptin receptor deficient (db/db) RBhigh cells. Scid mice were injected with wild-type (WT) or db/db RBhigh cells. At weeks 5 and 12, a group of five mice per experimental group was sacrificed for evaluation of cytokine production by colon cultures. Data are mean (SEM). *p<0.05, ***p<0.001 versus WT. IFN-γ, interferon γ; IL, interleukin; TGF-β, transforming growth factor β; MIP-2, macrophage inflammatory protein 2.
Figure 6
Figure 6
Altered cytokine production in lamina propria lymphocytes (LPL) of mice receiving leptin receptor deficient (db/db) RBhigh cells. Scid mice were injected with wild-type (WT) or db/db RBhigh cells. At weeks 5 and 12, a group of five mice per experimental group was sacrificed for evaluation of cytokine production by LPL stimulated with anti-CD3ε. Data are mean (SEM). ***p<0.001 versus WT. IFN-γ, interferon γ; IL, interleukin; MIP-2, macrophage inflammatory protein 2.
Figure 7
Figure 7
High expression of peroxisome proliferator activated receptor γ (PPARγ) in the colon of mice receiving leptin receptor deficient (db/db) RBhigh cells. PPARγ expression was evaluated in the colon of scid mice that had received wild-type (WT) or db/db RBhigh cells five or 12 weeks earlier and in control mice.
Figure 8
Figure 8
Cytokine production and T-bet expression in freshly sorted wild-type (WT) and leptin receptor deficient (db/db) RBhigh and RBlow cells. RBhigh and RBlow cells were isolated from the spleen of WT and db/db mice. Cells were stimulated with plate bound anti-CD3ε, in the absence (A, C) or presence (B, D) of soluble anti-CD28. Interferon γ (IFN-γ) (A, B) and interleukin 10 (IL-10) (C, D) levels were measured in culture supernatants. Data are mean (SEM) of four wells. ***p<0.001 versus WT RBhigh cells. (E) Expression of T-bet was evaluated by western blot in unstimulated WT and db/db RBhigh cells. Equal loading was evaluated using an antiactin antibody.
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