Interleukin-6 (IL-6) is required for normal liver regeneration, but the specific cellular source of this growth factor is unknown. We investigated whether this signal originates from the resident macrophage, the Kupffer cell. Using a murine model of bone marrow transplantation, we replaced recipient bone marrow-derived cells, including Kupffer cells, with cells of donor genetic phenotype. Recipients deficient in IL-6 (IL-6 ؊/؊ ) were lethally irradiated, then rescued with 10 7 donor bone marrow cells capable of expressing IL-6 (IL-6 ؉/؉ ). Conversely, IL-6 ؉/؉ recipients received IL-6 ؊/؊ marrow.

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These data demonstrate that depletion of T cells from rat marrow does not impair engraftment of HSCs, indirectly supporting the existence of FCs in rat marrow. Moreover, donor alphabeta- and gammadelta-TCR(+) T cells contribute to GVHD in a nonredundant fashion, although alphabeta-TCR(+) T cells are more potent as the effector cells. Finally, the level of donor chimerism is influenced by the composition of the graft, because recipients of marrow that contain alphabeta-TCR(+) T cells exhibited significantly higher donor chimerism compared to recipients of marrow depleted of both alphabeta- and gammadelta-TCR(+) T cells.

Rationale: Abdominal aortic aneurysm (AAA) is a permanent and localized dilatation of abdominal aorta with potentially fatal consequence of aortic rupture. No effective pharmacological approach has been identified to limit AAA progression and rupture. AAA is characterized by extensive aortic wall matrix degradation that contributes to arterial wall remodeling and eventual rupture, in which smooth muscle cell (SMC) phenotypic transition and matrix metalloproteinases (MMP), especially MMP2 and MMP9, play critical roles. Objective: Our previous study showed that adenosine deaminases acting on RNA 1 (ADAR1) regulates SMC phenotype, which prompted us to study if ADAR1 is involved in AAA development. Methods and Results: We used angiotensin II (Ang II) infusion ApoE-/- mouse model combined with ADAR1 global and SMC-specific knockout to study the role of ADAR1 in AAA formation/dissection. Aortic transplantation was conducted to determine the importance of vascular cell ADAR1 in AAA development/dissection. Primary cultured SMC were used to study how ADAR1 regulates the inflammatory SMC phenotype and MMP production/activity. Patient specimens were obtained to investigate the relevance of ADAR1 expression to human AAA disease. ADAR1 was induced in abdominal aortic SMC in both mouse and human AAA tissues. Heterozygous knockout of ADAR1 diminished the Ang II-induced AAA/dissection in ApoE-/- mice. Mouse aortic transplantation showed that ADAR1 in vascular cells was essential for AAA formation. SMC-specific ADAR1 knockout reduced experimental AAA formation/dissection. Mechanistically, ADAR1 interacted with HuR to increase the stability of MMP2 and MMP9 mRNA, leading to increased MMP levels and activities. Conclusions: ADAR1 is novel regulator of AAA development/dissection, and thus may represent a potentially new therapeutic target to hinder AAA growth and rupture.