305). Oddly enough, the dampener was known for its ability to enhance inflammation.
To find genes that unleash uncontrolled inflammation and pathways that inhibit them, the authors turned to mice whose cells overreact to inflammatory stimuli that trigger Toll-like receptors (TLRs). The mice, however, do not suffer ill effects from their overzealous response. One potential explanation, the authors reasoned, is that mutations in TLR response genes might be counterbalanced by mutations in regulatory genes.
The group has now mapped the phenotype of these mice to two loci. The first locus contained the gene for the interleukin receptor–associated kinase (IRAK) 2, which helps turn on inflammatory cytokine genes in TLR-activated cells. The second locus contained a gene encoding IRAK1-binding protein (IRAK1BP) 1, which was previously identified as an enhancer of some proinflammatory signals.
In cells from the easily inflamed mice, however, IRAK1BP1 partially suppressed their proinflammatory phenotype. TLR-activated macrophages from these mice turned on IRAK1BP1, which then suppressed the transcriptional activation of several cytokines. Macrophages from normal mouse strains, however, did not express IRAK1BP1 in response to TLR activation. The prior study suggesting a proinflammatory role for IRAK1BP1 relied on overexpression of the protein in a cell line; the role of endogenous IRAK1BP1 had not been explored.
The team found several differences between the IRAK1BP1 promoter sequence in normal and hyperreactive mice. But whether these differences determine the alternative expression of IRAK1BP1 is not clear. In normal mice, IRAK1BP1 might only kick in when other inflammation-suppressing mechanisms go awry.