Tumor necrosis factor α-induced proteins: natural brakes on inflammation.

Peggy Jacques and Dirk ElewautOne of the principal tasks of our immune systemis to protect our body against pathogens. Of equalimportance, however, is the capacity to preserve theintegrity of the host by protecting against autoimmunity.To accomplish this, a number of regulatory pathwayshave been revealed. They include certain regulatoryT cell subsets, such as FoxP3 Treg cells, natural killerT cells, and Tr1 cells, as well as other cell types, such ascertain macrophage subsets. While some of these occurnaturally as the immune system develops, interestingly,certain subsets may be actively induced in adults. Thishas sparked interest in their potential use in therapeuticapproaches. Also at the cellular level, a number ofproteins with antiinflammatory capacity have been dis-covered, some of which are induced in response to theproinflammatory cytokine tumor necrosis factor (TNF).TNF operates both upstream and downstream ofdiverse signaling cascades, and numerous proteins areinduced in response to TNF. In recent years, some ofthese so-called TNF -induced proteins (TNFAIPs) havegained a lot of interest. One of these proteins is A20, orTNFAIP-3, a deubiquitinating protein that negativelyregulates NF- B–dependent gene expression in re-sponse to different immune-activating stimuli, includingTNF, interleukin-1 (IL-1), and in response to triggeringof Toll-like receptors (TLRs) and nucleotide-bindingoligomerization domain–containing protein 2 (NOD-2)receptor 1. A20 is considered to inhibit NF- B func-tion by deubiquitinating specific NF- B signaling mole-cules, such as receptor-interacting protein 1 (RIP-1),RIP-2, and TNF receptor–associated factor 6 (TRAF-6).Several single-nucleotide polymorphisms in the humanTNFAIP-3 locus have been shown to be associated withincreased susceptibility to rheumatoid arthritis, type 1diabetes mellitus, systemic lupus erythematosus, celiacdisease, Crohn’s disease, psoriasis, and multiple sclerosis(for review, see ref. 1).Another TNF-induced protein, TNFAIP-5, orpentraxin 3, is expressed in rheumatoid arthritis synovialtissue and in astrocytes from patients with Alzheimer’sdisease (2,3), while the apoptosis regulator TNFAIP-8contains a death-effector domain and is capable ofinhibiting caspase-mediated apoptosis (4). Knock-downof TNFAIP-8 expression in tumor cells decreases theironcogenicity, which suggests that it may be involved incarcinogenesis (5). TNFAIP-6 (TNF -stimulated gene 6[TSG-6]), a protein involved in cell–cell and cell–matrixinteractions, is expressed within the synovium and car-tilage of arthritic joints and is thought to play a protec-tive role in articular inflammation (6). It further inhibitsRANKL-induced osteoclast differentiation and activa-tion (7).The important roles of these proteins in themammalian immune system have been demonstrated inmice, where a deficiency in the proteins generally leadsto systemic inflammation. Mice fully deficient in A20spontaneously develop multiple organ inflammation andcachexia and die within 2 weeks of birth (8). Micedeficient in TNFAIP-8–like 2 (TIPE-2; a member of theTNFAIP-8 family) develop multiple organ inflammationand splenomegaly, are hypersensitive to septic shock,and die prematurely (9).TNF -induced adipose-related protein (TIARP),also called 6-transmembrane protein of prostate 2(STAMP-2) or the human homolog 6-transmembraneepithelial antigen of prostate 4 (STEAP-4), belongs to afamily of 4 mammalian proteins that were all originallycharacterized in the prostate, including STAMP-1(STEAP-2), STEAP, and STEAP-3 (pHyde) (10,11).The expression of TIARP/STAMP-2 dramatically in-creases during TNF exposure, and yet also during thecourse of adipose differentiation, as demonstrated in the3T3-L1 preadipose cell line (11). Tissue distribution ofTIARP messenger RNA is not restricted to white andbrown adipose tissues, but is also detectable in liver,kidney, heart, and skeletal muscle.