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* Department of Medicine I,
Department of Surgery, and
Institute for Infection Biology, Microbiology and Virology, Campus Benjamin Franklin, and
Institute for Microbiology and Hygiene, Campus Charité-Mitte and Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, Berlin, Germany; and
¶ Department of Immunology, University of Toronto, Toronto, Canada
Translocation of bacteria into the mesenteric fat during intestinal inflammation and the expression of functional TLR1–9 in murine preadipocytes and adipocytes suggest an active role for these cells in innate immunity. The present study focuses on nucleotide oligomerization domains 1 and 2 representing intracellular pattern recognition receptors that sense motifs derived from bacterial peptidoglycans. On mRNA level nucleotide oligomerization domain 1 was found to be constitutively expressed in the preadipocyte cell line 3T3L1 and in primary preadipocytes isolated from murine mesenteric fat, while nucleotide oligomerization domain 2 was only weakly expressed by these cells. Treatment with lactyl-tetra-diaminopimelic acid, muramyl dipeptide, LPS, IL-1β, and TNF-
did not affect cellular nucleotide oligomerization domain 1 mRNA amounts. Except muramyl dipeptide, all factors significantly increased nucleotide oligomerization domain 2 mRNA in mesenteric fat preadipocytes after 4 h. However, specific stimulation of nucleotide oligomerization domain 1 induced IL-6 synthesis in preadipocytes from wild-type or TLR2/4-deficient mice. Confirming nucleotide oligomerization domain 1 specificity, transfection of nucleotide oligomerization domain 1-specific small interfering RNA significantly blocked the effect of lactyl-tetra-diaminopimelic acid on IL-6 production. With specific inhibitors and a NF-
B reporter plasmid, nucleotide oligomerization domain 1-mediated activation of NF-B was shown to be responsible for the induction of IL-6 in preadipocytes. In addition, expression of functional nucleotide oligomerization domain 1 could be confirmed in primary human preadipocytes. In summary, we here identified preadipocytes as a novel cell population expressing nucleotide oligomerization domains 1 and 2. Not regulated on transcriptional level, nucleotide oligomerization domain 1 in preadipocytes serves as a sensor for bacterial degradation products and triggers proinflammatory effector responses. Thus, our results further strengthen the allocation of the mesenteric fat and especially of preadipocytes to the innate immune system.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 The contributions of M.M.H. and S.B. were financed by Fritz-Thyssen Foundation Grant A.Z. 10.05.2.194 and German Research Foundation Grant SFB633/A12.
2 Address correspondence and reprint requests to Dr. Britta Siegmund, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Medical Department I, Hindenburgdamm 30, 12200 Berlin, Germany. E-mail address: britta.siegmund{at}charite.de
3 Abbreviations used in this paper: LT-DAP, lactyl-tetra-diaminopimelic acid; MDP, peptidoglycan muramyl dipeptide; iE-DAP, 
-D-glutamyl-meso-diaminopimelic acid; iE-Lys, -D-glutamyl-lysine; WT, wild type; siRNA, small interfering RNA.
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