Arthritis suppression by TNF alpha regulators

drj writes "Many rheumatoid arthritis patients are helped by treatments that block the inflammatory cytokine TNF alpha. TNF alpha production is reduced by two proteins that bind AU-rich regions of mRNA: TIA-1 inhibits protein translation and TTP promotes mRNA degradation. Mice deficient in either TIA-1 or TTP (gene “knockouts”) develop arthritis. Not surprisingly, Phillips and colleagues show that TIA-1/TTP double knockout mice develop worse arthritis. Single knockout macrophages contain more TNF alpha protein than normal macrophages and double knockout macrophages contain much more, most markedly the membrane bound form (mTNF alpha). Surprisingly, much less TNF alpha protein is secreted by double knockout macrophages than either single knockout, suggesting TIA-1 and TTP influence secretion or mTNF alpha processing. The investigation turned to the less usual suspects, neutrophils, which also make TNF alpha and are extraordinarily abundant in the bone marrow of double knockout mice. Indeed, activated bone marrow cells from double knockout mice express much more TNF alpha than single TTP knockout macrophages. However, purified neutrophils from TTP knockout mice show only a modest increase and double knockout show no further increase, leaving the origin of the increased TNF obscure. Although failing to establish a complete mechanism, this investigation demonstrates several important interactions and represents the kind of analysis that is necessary to dissect complex disease genetics.
Phillips et al. PNAS 101:2011-2016. February 17, 2004. Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor alpha, cyclooxygenase 2, and inflammatory arthritis Kristine Phillips, Nancy Kedersha, Lily Shen, Perry J. Blackshear, and Paul Anderson
Additional information: Macrophages and neutrophils were activated with bacterial endotoxin, LPS. Double knockout mice are born runts and remain about half the weight of single knockout or normal mice.