Nucleotide Oligomerization Domains 1 and 2: Regulation of Expression and Function in Preadipocytes

Abstract

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-α 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-κB reporter plasmid, nucleotide oligomerization domain 1-mediated activation of NF-κB 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.

Pivotal role of NOD2 in inflammatory processes affecting atherosclerosis and periodontal bone loss

“…NOD2 expression and unique functions have also been described in other cell types, including adipocytes, gingival, pulp and periodontal fibroblasts, oral epithelial cells, and vascular endothelial cells (20)(21)(22)(23)(24)(25). However, the precise role of NOD2 in chronic inflammatory diseases remains unclear.…”

The protein Nod2: An innate receptor more complex than previously assumed

“…While these data have to be further investigated, they elicit the question concerning the role of Nod2 in other cell types than monocytes/macrophages, dendritic and epithelial cells. Indeed, Nod2 has been shown to be expressed in neutrophils [93], preadipocytes [94], osteoblasts [95], renal tubular epithelial cells [96],. .…”

Significant Differences Between Crohn’s Disease and Ulcerative Colitis Regarding the Impact of Body Mass Index and Initial Disease Activity on Responsiveness to Azathioprine: Results from a European Multicenter Study in 1,176 Patients

“…It has become clear that, rather than just an inert tissue devoted to energy storage, adipose tissue must be considered as an active player in the physiologic and pathophysiologic regulation of immunity and inflammation [17,28]. In addition, recent data suggest that adipose tissue must also be considered as part of the innate immune system interacting with luminal bacterial antigens [21].…”

“…Currently, the concept of an intricate relationship between fatty metabolism and the immune system is evolving [16,17], and recent clinical and experimental evidence has elucidated a potentially important role of the mesenterial adipose tissue and adipokines in the pathogenesis of colitis [18][19][20]. The translocation of bacteria into the mesenteric fat during intestinal inflammation and the expression of Toll-like receptors on adipocytes suggest that adipose tissue should be considered as part of the innate immune system [21].…”