Aberrant Production of IL-12 by Macrophages from Several Autoimmune-Prone Mouse Strains Is Characterized by Intrinsic and Unique Patterns of NF-κB Expression and Binding to the IL-12 p40 Promoter

Abstract

Intrinsic defects in macrophage (Mφ) cytokine production characterize many autoimmune-prone mouse strains. Aberrant levels of IL-12, for example, are produced by Mφ isolated from young mice prone to lupus (MRL and NZB/W) and diabetes (nonobese diabetic (NOD)) well before the appearance of disease signs. Evaluation of the possible mechanism(s) underlying the abnormal regulation of IL-12 in these strains revealed novel patterns of Rel family protein binding to the unique p40 NF-κB site in the IL-12 p40 promoter, whereas binding patterns to Ets and CCAAT enhancer binding protein/β sites were normal. In particular, the heightened production of IL-12 by NOD Mφ is associated with elevated levels of the trans-activating p50/c-Rel (p65) complex compared with the nonfunctional p50/p50 dimer. Conversely, the dramatically impaired production of IL-12 by both NZB/W and MRL/+ Mφ is associated with a predominance of p50/p50 and reduced p50/c-Rel(p65) binding. Mechanistically, the unique pattern seen in the lupus strains reflects elevated p50 and reduced c-Rel nuclear protein levels. In NOD extracts, the level of c-Rel is elevated compared with that in lupus strains, but not when compared with that in normal A/J. However, the extent of c-Rel tyrosine phosphorylation noted in NOD extracts is more than double that seen in any other strain. Levels of p65 were similar in all strains tested. These findings reveal that a common mechanism, involving dysregulation of c-Rel and p50, may be used to determine the aberrant IL-12 levels that have the potential to predispose specific mouse strains to systemic or organ-specific autoimmunity.

Dendritic Cells from Lupus-Prone Mice Are Defective in Repressing Immunoglobulin Secretion

“…This could reflect a defect in the TLR signaling pathway or possibly the selective formation of NF-B complexes that are less transcriptionally active. Aberrant cytokine production and abnormal NF-B activity in T cells and M s from lupus-prone mice and lupus patients have been associated with decreased p65, increased p50 homodimers which are more inhibitory to gene transcription, reduced binding of p50/c-Rel and p65 NF-B complexes, and increased activity of histone deacetylases (35,36). Unfortunately we could not identify the NF-B subunits formed by MRL/lpr DCs because DNA binding was not observed at levels sufficient for supershifting.…”

Regulation of cytokine production during phagocytosis of apoptotic cells

“…Specifically, IL-12 administration exacerbates autoimmune phenomena by inducing the differentiation of Th1 autoreactive cells [29,30] whereas the lack of IL-12/IL-23 p40 in genetically deficient mice or mice treated with anti-IL-12 antibody abrogated diseases in experimental models of autoimmunity such as insulin-dependent diabetes mellitus (IDDM) in NOD mice [31,32], experimental allergic encephalomyelitis (EAE) [33,34], experimental autoimmune uveitis (EAU) [35,36], and collagen-induced arthritis (CIA) [37]. Aberrant levels of IL-12 are produced by macrophages isolated from young mice prone to lupus (MRL and NZB/W) [38]. The diabetes-associated quantitative trait locus, Idd4, was found to be responsible for the IL-12 p40 overexpression in nonobese diabetic (NOD) mice.…”

Autologous umbilical cord blood infusion for type 1 diabetes

“…[17]. In terms of the cellular basis for this immunoregulatory failure, it is key to note (albeit somewhat controversial) that both NOD mice and patients with T1D have potential deficiencies in at least two T cell populations intimately involved in immune regulation; NKT cells and CD4+CD25+ or so called "regulatory" T cells (Treg) [18][19][20][21][22]. In addition to defects in T cell based immune regulation, developmental and functional defects have also been reported in B-lymphocytes as well as antigen presenting cells (APC) of both NOD mice and human's with T1D; including those of differentiation and function of macrophages and DC [23][24][25][26][27][28][29].…”

“…Nevertheless, morbidity was still an issue. Male patients had semen samples stored prior to treatment to preserve fertility, all patients received antimicrobial and antifungal prophylaxis, mean hospital stay was 19.2 days (range [15][16][17][18][19][20][21][22][23][24], and nearly all patients experienced the common transplantationrelated complications of febrile neutropenia, nausea, vomiting, and alopecia.…”