Abstract
The anti-inflammatory adipokine CTRP-3 might affect innate immune reactions such as NOD1. The impact of CTRP-3 on NOD1-mediated inflammation in adipocytes and monocytic cells as well as on NOD1 expression was investigated. Murine 3T3-L1 pre-adipocytes and adipocytes as well as human THP-1 monocyte-like cells were co-stimulated with the synthetic NOD1 agonist Tri-DAP and recombinant CTRP-3. Gonadal adipose tissue and primary adipocytes were obtained from a murine model carrying a knockout (KO) of CTRP-3 in adipocytes but not in stroma-vascular cells. Wildtype mice with lipopolysaccharide (LPS)-induced elevated NOD1 expression were treated with CTRP-3. Secreted inflammatory cytokines in cell supernatants were measured by ELISA and mRNA levels were quantified by RT-PCR. Pro-inflammatory chemokine and cytokine secretion (MCP-1, RANTES, TNFα) was induced by NOD1 activation in adipocytes and monocyte-like cells, and MCP-1 and RANTES release was effectively inhibited by pre-incubation of cells with CTRP-3. CTRP-3 also antagonized LPS-triggered induction of NOD1 gene expression in murine adipose tissue, whereas adipocyte CTRP-3 deficiency upregulated NOD1 expression in adipose tissue. CTRP-3 is an effective antagonist of peptidoglycan-induced, NOD1-mediated inflammation and of LPS-induced NOD1 expression. Since basal NOD1 expression is increased by adipocyte CTRP-3 deficiency, there have to be also inflammation-independent mechanisms of NOD1 expression regulation by CTRP-3.
Highlights
C1q/TNF-related protein (CTRP)-3 is a family member of adiponectin paralogs (CTRP1-15) [1] that is mainly expressed in adipose and gonadal tissues and in kidney [2].It represents an adipokine with pleiotropic functions, including regulation of cell proliferation in different cell types [3, 4] and predominantly beneficial metabolic and immunomodulatory effects [5,6,7]
3T3-L1 fibroblasts/pre-adipocytes were stimulated with Tri-DAP (10 ng/ml) in order to test for a NOD1mediated inflammatory response
THP-1 cells were differentiated to macrophage-like cells by phorbol 12-myristate 13-acetate (PMA) treatment and stimulated with Tri-DAP (10 ng/ml), resulting in increased MCP-1 and TNFα levels in cell supernatants after 18 h (p < 0.001; Fig. 2A and B)
Summary
C1q/TNF-related protein (CTRP)-3 is a family member of adiponectin paralogs (CTRP1-15) [1] that is mainly expressed in adipose and gonadal tissues and in kidney [2] It represents an adipokine with pleiotropic functions, including regulation of cell proliferation in different cell types [3, 4] and predominantly beneficial metabolic and immunomodulatory effects [5,6,7]. Mechanisms of host defense against tissue damage and exogenous pathogens are largely based on various classes of pattern recognition receptors (PRRs) [12] These receptors recognize microbial and pathogen-associated molecular patterns (PAMPs) as well as endogenous signals released by damaged cells, the socalled damage-associated molecular patterns (DAMPs) [13, 14]. Upon recognition of PAMPs or DAMPs, PRRs in immune cells induce a predominantly pro-inflammatory gene expression profile, including cytokines, chemokines, interferons, and anti-microbial peptides
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