TL1A Both Promotes and Protects from Renal Inflammation and Injury

Abstract

Death receptor 3 (DR3), a member of the TNF receptor (TNFR) superfamily, is induced in human renal tubular epithelial cells (TEC) in response to injury. This study examined the expression and actions of TL1A, the principal ligand for DR3. In histologically normal tissue from biopsy or nephrectomy specimens of renal allografts, TL1A mRNA and protein were expressed in vascular endothelial cells but not in TEC. In specimens of acute or antibody-mediated allograft rejection, vascular endothelial cells and infiltrating leukocytes expressed increased TL1A mRNA and protein, but TEC expressed TL1A protein without mRNA, consistent with uptake of exogenous ligand. Addition of TL1A to organ cultures of human or mouse kidney caused activation of NF-B, expression of TNFR2, activation of caspase-3, and apoptosis in TEC. Inhibition of NF-B activation increased TL1A-mediated caspase-3 activation and apoptosis of TEC, but it did not reduce the induction of TNFR2. In organ culture of DR3-deficient mouse kidneys, addition of TL1A induced TNFR2 but did not activate NF-B and did not increase apoptosis of TEC. These data suggest that TL1A may contribute to renal inflammation and injury through DR3-mediated activation of NF-B and caspase-3, respectively, but that an unidentified receptor may mediate the NF-B-independent induction of TNFR2 in TEC.

FOXO3a Regulates Oxygen-responsive Expression of Tumor Necrosis Factor Receptor 2 in Human Dermal Microvascular Endothelial Cells

“…As noted earlier, we have observed induction of TNFR2 in organ culture in response to TNF and to TL1A (20,29). The TNF response appears to be mediated through TNFR2, as assessed by the response to receptor-specific mutein forms of TNF (20), and the response to TL1A occurs in mouse kidney tissue harvested from DR3-deficient mice (29), DR3 being the only known receptor for TL1A.…”

“…The TNF response appears to be mediated through TNFR2, as assessed by the response to receptor-specific mutein forms of TNF (20), and the response to TL1A occurs in mouse kidney tissue harvested from DR3-deficient mice (29), DR3 being the only known receptor for TL1A. In both cases, the induction of TNFR2 was not reduced by effective pharmacological inhibition of NF-B activation (29). In addition to the FOXO3a site we have identified in this study, there are a number of other potential regulatory sequences in the 5Ј-flanking region of the human (30) and mouse (31) TNFR2 gene, including motifs for binding of transcription factors T cell factor 1, Ikaros, AP-1, CK-2, interleukin-6 receptor E, ISRE, GAS, NF-B, Sp1, CREB, Yi, and YY1.…”

TNF-like Ligand 1A (TL1A) Gene Knockout Leads to Ameliorated Collagen-Induced Arthritis in Mice: Implication of TL1A in Humoral Immune Responses

“…As a consequence, in the absence of DR3 or TL1A, Th cells could still be developed to near-normal levels. Alternatively, DR3 and TL1A are not utterly essential in Th cell development; the enhanced Th cell development in the presence of nonphysiological high doses of exogenous or transgenic TL1A is due to its cross-reaction with other TNFR superfamily members (12). The results from CIA mice treated with TL1A-neutralizing Ab favor the first explanation (23).…”

“…DR3 is detectable on T cells, NK cells, NKT cells, osteocytes, renal tubule epithelial cells, and in vitro plasma cells, but primary B cells express very low levels of DR3 (3,(11)(12)(13). Previous studies of the immunological functions of TL1A and DR3 primarily focused on T cells, NK cells, and NKT cells (3,12,(14)(15)(16). In addition to DR3, decoy receptor 3 also could bind to TL1A in humans and blocks the interaction between TL1A and DR3 (1).…”

Signaling Activated by the Death Receptors of the TNFR Family

“…DR3 has a prominent role in the regulation of the immune system as it contributes to efficient T cell activation, mainly during inflammatory response 89,90 . However, in non-hematopoiteic cells DR3 apparently plays also an active role in the development of antigen-induced arthritis (AIA) and contributes to human renal tubular epithelial cells (TEC) destruction in response to injury 91,92 . DR6, another highly glycosylated 93 and till this year an orphan receptor is expressed both on hematopoietic and neuronal cells.…”