Leptin Promotes Differentiation and Survival of Human Dendritic Cells and Licenses Them for Th1 Priming

Abstract

Leptin is an adipocyte-derived hormone/cytokine that links nutrition, metabolism, and immune homeostasis. Leptin is capable of modulating several immune responses. However, the effect of leptin on dendritic cells (DCs) has not yet been recognized. Because DCs are instrumental in the development of immune responses, in this study, we evaluated the impact of leptin on DC activation. We demonstrated the presence of leptin receptor in human immature and mature DCs both at mRNA and protein level and its capacity to transduce leptin signaling leading to STAT-3 phosphorylation. We found no consistent modulation of DC surface molecules known to be critical for their APC function in response to leptin. In contrast, we found that leptin induces rearrangement of actin microfilaments, leading to uropod and ruffle formation. At a functional level, leptin up-regulates the IL-1β, IL-6, IL-12, TNF-α, and MIP-1α production. Coincident with this, leptin-treated DCs stimulate stronger heterologous T cell responses. Furthermore, we found that leptin down-regulates IL-10 production by DCs and drives naive T cell polarization toward Th1 phenotype. Finally, we found that leptin partly protects DCs from spontaneous and UVB-induced apoptosis. Consistent with the antiapoptotic effect of leptin, we observed the activation of NF-κB and a parallel up-regulation of bcl-2 and bcl-xL gene expression. These results provide new insights on the immunoregulatory function of leptin demonstrating its ability to improve DC functions and to promote DC survival. This is of relevance considering a potential application of leptin in immunotherapeutic approaches and its possible use as adjuvant in vaccination protocols.

Involvement of leptin signaling in the survival and maturation of bone marrow‐derived dendritic cells

“…Therefore, in addition to our finding of reduced DC yield in db/db BM cultures, these results argue for a physiological role for leptin signaling in DC generation. Our observations of increased apoptosis of db/db DC support the notion that leptin signaling acts as a pro-survival factor in immune cells [13,27]. Although the exact molecular mechanism involved remains to be elucidated, the skewed balance of Bcl-2 family genes towards upregulated expression of the pro-apoptotic member Bim and down-regulation of the anti-apoptotic Bcl-2 suggests a potential role of leptin signaling in modulating Bcl-2 family proteins.…”

“…samples, consistent with previous findings in human DC [13]. Transcripts of DC from normal mice displayed a product of correct size (413 bp) for functional Ob-Rb, whereas those from db/db DC showed a larger product (519 bp) due to the gene targeting with an insertion [14][15][16].…”

“…Leptin has been shown to activate the PI3K/Akt pathway in a variety of cell types, including mononuclear cells and human DC, through interaction of phosphorylated Janus kinase 2 on the intracellular domain of Ob-R with insulin receptor substrate-1, followed by association with the p85 subunit of PI3K [13,43]. NF-jB, one of the downstream targets of the PI3 K/Akt pathway, is known to be a key regulator of DC survival, development, maturation and APC function [22].…”

“…Upon presentation of processed antigens to T cells, the different stimuli that induce maturation of DC determine the production of various cytokines that facilitate the polarization of T cell responses. A recent study by Mattioli et al demonstrated that recombinant leptin can promote differentiation and survival of human DC and drive T cell polarization toward a Th1 phenotype [13]. However, it remains to be established whether leptin signaling plays a physiological role in DC survival and maturation.…”

Leptin in immuno-rheumatological diseases

“…24,36 In fact, leptin receptors can also be found in different tissues and immune cell types, including various subpopulations of T and B lymphocytes, dendritic cells, monocytes, neutrophils, macrophages and natural killer (NK) cells. 18,[37][38][39][40][41] The cytokine-like structural characteristic of leptin is implicative of its function in regulating immune responses. This concept is discussed in detail in the present review.…”