LAUSR

Human CTRP4 is a member of the C1q/TNF-related protein (CTRP) superfamily. This family, originally identified by Lodish and coworkers, is a highly conserved family consisting of secreted proteins that were cloned on the basis of an adiponectin homology sequence.1 Up to now, 15 members have been identified in CTRP superfamily (CTRP1–CTRP15) (Figure 1). Those, together with adiponectin, leptin and resistin, are collectively known as the adipocytokine superfamily.2 CTRPs usually assume a homotrimeric structure and each subunit is composed of an N-terminal signal peptide, a short variable region, a collagen domain and a C-terminal C1q globular domain.3 Accumulating evidence has demonstrated that CTRPs play important regulatory roles in inflammation, metabolism and tumor angiogensis. We first reported the cloning of CTRP4 through bioinformatic analysis and high-throughput screening in 2011.4 Using a NF-κB luciferase reporter gene screening, we found that CTRP4 was a potent activator of NF-κB in 293T, HeLa and HepG-2 cells. CTRP4 contains a classical N-terminal signal peptide, suggesting that it may be secreted as a cytokine. In support, recombinant CTRP4 can effectively activate both NFκB and IL-6/STAT3 signaling pathways and promote the secretion of IL-6 and TNF. In contrast to a single C1q globular domain in other members of the CTRP4 superfamily, two such domians are found in CTRP4. They share 51% homology to each other, while the similarity is only 27–30% between them and the complement component C1q.5 CTRP4 appears to be well conserved in evolution since human and mouse CTRP4 share over 90% homology in amino-acid sequence. As much as its expression pattern is concerned, CTRP4 is mainly detected in brain, fat and bone marrow stem cells. In addition, it is present in the blood as a circulating protein. In order to explore its physiological functions, we have prepared both polyclonal and monoclonal antibodies against CTRP4. Moreover, a mouse strain was also generated for transgenic expression of CTRP4.6–8 Contradictory to the findings from in vitro studies, in vivo experiments with various inflammatory models have demonstrated that CTRP4 primarily exerted an antiinflammatory activity. In the DSSinduced mouse colitis model,9 transgenic expression of CTRP4 significantly relieved the symptoms and prolonged the survival of mice. Similar attenuating effects were also observed after administration of recombinant CTRP4. In an azoxymethane (AOM)/repeated administration of dextran sodium sulfate (DSS)induced inflammatory cancer model, CTRP4 transgenic mice displayed resistance to tumorigenesis.10 Fewer transgenic mice developed colonic tumors and the tumors arising in the transgenic mice had smaller volume and were mainly adenoma instead of adenocarcinoma. Presumably, the reduced occurrence of tumor might be related to suppressed inflammation. Of note, NFκB and STAT3 activation was significantly reduced in colitis specimens from the CTRP4 transgenic mice.11 The CTRP4’s roles in promoting tumor cell proliferation in vitro and suppressing inflammation and tumorigenesis in vivo indicate that CTRP4 may have different functions depending on cell types, receptors and/or cell context. In the effort of searching for the cell types that mediate CTRP4’s anti-inflammatory role, we found that rhCTRP4 treatment suppressed Lipopolysaccharide-induced STAT3 and NF-kB activation and pro-inflammatory cytokine production in bone marrowderived macrophages. Thus, the anti-inflammatory role of CTRP4 can be at least realized by directly or indirectly suppressing macrophage activation in response to pathogen-associated molecular patterns. As a member of adipocytokine superfamily, our results further indicate that CTRP4 is an important regulator in glucose and lipid metabolism. CTRP4 transgenic mice showed higher level of food intake but were highly resistant to obesity and hyperglycemia. Compared to wild-type mice, CTRP4 transgenic mice Department of Immunology, Key Laboratory of Medical Immunology (Ministry of Health), School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China E-mail: [email protected] Received: 30 June 2017; Accepted: 22 August 2017 Cellular & Molecular Immunology (2017) 14, 868–870 & 2017 CSI and USTC All rights reserved 2042-0226/17 $32.00