Membrane-Bound TNF Supports Secondary Lymphoid Organ Structure but Is Subservient to Secreted TNF in Driving Autoimmune Inflammation

Abstract

Mice without secreted TNF but with functional, normally regulated and expressed membrane-bound TNF (memTNF(Delta/Delta) mice) were created by knocking-in the uncleavable Delta 1-9,K11E TNF allele. In contrast to TNF-deficient mice (TNF(-/-)), memTNF supported many features of lymphoid organ structure, except generation of primary B cell follicles. Splenic chemokine expression was near normal. MemTNF-induced apoptosis was mediated through both TNF-R1 and TNF-R2. That memTNF is suboptimal for development of inflammation was revealed in experimental autoimmune encephalomyelitis. Disease severity was reduced in memTNF(Delta/Delta) mice relative to wild-type mice, and the nature of spinal cord infiltrates resembled that in TNF(-/-) mice. We conclude that memTNF supports many processes underlying lymphoid tissue structure, but secreted TNF is needed for optimal inflammatory lesion development.

Transmembrane TNF protects mutant mice against intracellular bacterial infections, chronic inflammation and autoimmunity

“…S1). These results confirm the requirement for soluble TNF in the lethality observed in the LPS/D-gal shock model [17,40].…”

“…S1). These results confirm the requirement for soluble TNF in the lethality observed in the LPS/D-gal shock model [17,40].Having established proper regulation of tmTNF D1-12 at both the transcriptional and the expression levels, we further addressed the issue of bioactivity by examining its ability to promote thymocyte proliferation. It has been shown that signaling through p75TNFR, but not p55TNFR, is essential to enhance the proliferation of mitogen-activated thymocytes [41].…”

“…In addition, overexpressed tmTNF appears fully capable of supporting p55TNFR-dependent follicular dendritic cell (FDC) and B cell follicle development [16]. In contrast, regulated expression of a mutant tmTNF gene in knockin mice revealed a suboptimal role for tmTNF in supporting development of autoimmune inflammation in EAE, while the same molecule was highly inefficient in supporting correct secondary lymphoid organ structure [17]. It appears therefore that overexpressed tmTNF represents fully the activities of WT TNF, whereas only a subset of these activities is affected when expression of tmTNF is physiologically regulated on the membrane.…”

“…Moreover TNF-deficient mice exhibit defects in the formation of different MU populations and of the sinus lining cells of the splenic marginal zone [42]. Ruuls et al, using the mutant memTNF D1--9,K11E mice, previously reported that membrane TNF is sufficient to drive proper localization and development of components of the marginal zone and splenic chemokine expression but that it fails to support generation of B cell follicles and GC [17]. Although we have not addressed chemokine expression in our system, we have not observed any significant differences in splenic marginal zone organization between Tnf tm/tm and Tnf -/-mice.…”

Sex specifically associated promoter polymorphism in multiple sclerosis affects interleukin 4 expression levels

“…[20][21][22] Th2-like expression profiles were induced by addition of hrIL4 and a-INFg to the cell culture and Th1-like conditions by tumor necrosis factora addition, respectively. [23][24][25][26][27] Cells without stimulation were used as control. IL4-stimulated Jurkat cells showed significantly different levels of luminescence for the tested constructs, with the T variation exceeding the intensity of the C allele (Statistical Product and Service Solutions (SPSS)-Tukey test, Po0.05) as well as the vector without insert (SPSS-Tukey test, Po0.002) (see Figure 1).…”