Interferon-inducible Ifi200-family genes in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is the prototype of complex autoimmune diseases. Studies have suggested that genetic, hormonal, and environmental factors contribute to the development of the disease. Interestingly, several recent studies involving SLE patients and mouse models of the disease have suggested a role for interferon (IFN)-stimulated genes (ISGs) in the development of SLE. One family of ISGs is the Ifi200-family, which includes mouse (Ifi202a, Ifi202b, Ifi203, Ifi204, and Ifi205) and human (IFI16, MNDA, AIM2, and IFIX) genes. The mouse genes cluster between serum amyloid P-component (Apcs) and alpha-spectrin (Spna-1) genes on chromosome 1 and the human genes cluster in syntenic region 1q23. The Ifi200-family genes encode structurally and functionally related proteins (the p200-family proteins). Increased expression of certain p200-family proteins in cells is associated with inhibition of cell proliferation, modulation of apoptosis, and cell differentiation. Our studies involving generation of B6.Nba2 congenic mice, coupled with gene expression analyses, identified the Ifi202 as a candidate lupus-susceptibility gene. Importantly, recent studies using different mouse models of SLE have suggested that increased expression of Ifi202 gene (encoding p202 protein) in immune cells contributes to lupus susceptibility. Consistent with a functional role for the p202 protein in lupus susceptibility, increased levels of IFI16 protein in human SLE patients are associated with the diseases. This review summarizes recent findings concerning the regulation and role of p200-family proteins in the development of SLE.

Figure 1

Total cell extracts from splenocytes isolated from age-matched MRL^+/+ (lanes 1–3) or MRL^lpr/lpr (lanes 4–6) mice were analyzed by immunoblotting using antibodies specific to the indicated proteins.

Figure 2

A comparison of the 5’-regulatory sequences of the Ifi202 gene between C57BL/6 (B6) and NZB mice. A complete nucleotide sequence for the B6 mice is shown and a sequence for the NZB mice is shown only when it is either polymorphic or there is an insertion of nucleotides.

Figure 3

The presence of a typical TATA sequence in the NZB allele is predicted to result in higher basal and induced (induced by IFN, or IL-6) levels of transcription of the Ifi202 gene in the B6.Nba2 congenic mice.

Figure 4

A comparison of the amino acid sequences of the p202 protein, which was previously published (ref. ; the sequence was derived from mouse EAT cell line) by us, with that of the NZB mice derived p202 protein sequence. A complete amino acid sequence of the p202 protein from EAT cell line is shown and the sequence for the NZB-derived p202 protein is shown only when it is polymorphic.