Interleukin-12 (IL-12) orchestrates acquired resistance in intracellular

Hereditary factors are thought to be responsible for impaired tendon function and joint laxity. The present study investigated the genotypic variability of knee laxity and stiffness and tendon mechanical and geometric properties among 16-week-old female A/J, C57BL/6J (B6), and C3H/HeJ (C3H) inbred mice. In one group of mice, knee mechanics were quantified using a custom loading apparatus enabling translation of the tibia against a stationary femur. In a second group, flexor digitorum longus and Achilles tendons from the left hind limb underwent biomechanical testing, while those of the contralateral limb were analyzed histologically for determination of crosssectional area. Our results demonstrate that tendon and joint mechanics varied significantly among the inbred mouse strains, indicating that biomechanical properties are genetically determined. A/J mouse knees exhibited greater laxity (p < 0.001) and lower stiffness (p < 0.001) compared to those of the B6 and C3H mice. The genotypic differences in whole joint properties were similar to those of the tendons' structural biomechanical traits. Although body mass did not differ (p > 0.2) among the three strains, significant genotypic differences were found at the whole tendon, material quality, and morphological levels of the tissue hierarchy. Furthermore, genetic regulation of tendon mechanical properties varied with anatomic site. Patterns of genotypic differences in tendon size were not consistent with those of biomechanical properties, suggesting that unique combinations of structural and compositional factors contribute to tendon growth, adaptation, and development. Therefore, the three inbred strains constitute a useful experimental model to elucidate genetic control of structure-function relationships in normal and healing tendons and ligaments.

Leishmania donovani-infected interleukin-13؊/؊ BALB/c mice showed impaired initial gamma interferon secretion and incomplete granuloma assembly at parasitized liver foci. Nonetheless, control of early parasite replication, resolution of liver infection, and responsiveness to antileishmanial chemotherapy were intact. By itself, interleukin-13 does not appear to materially influence acquired resistance in this intracellular infection.In experimental visceral leishmaniasis, host defense against intracellular Leishmania donovani is T cell dependent and involves a range of T-cell-and macrophage-activating cytokines (15,16,25). In L. donovani infection in the liver, interleukin-12 (IL-12) and gamma interferon (IFN-␥) figure prominently in granuloma assembly, macrophage activation, and parasite killing, driving acquired resistance and eventual near resolution of infection (4,12,15,16,23,26). In addition, the same inflammatory response supports the efficacy of conventional antileishmanial chemotherapy, pentavalent antimony (Sb) (15).L. donovani infection also provokes expression of Th2-celltype cytokines (IL-4, IL-10, and IL-13) and transforming growth factor ␤ (18), ordinarily considered counterbalancing, suppressive factors. These cytokines probably limit tissue injury but to various degrees also derail Th1-cell responses, deactivate macrophages, and promote infection (3,9,11,17,19,27). In L. donovani-infected, susceptible, wild-type (WT) BALB/c mice, neutralization or receptor blockade has demonstrated a striking deactivating effect for IL-10, modest suppressive roles for transforming growth factor ␤ and IL-13, and no role for . Nevertheless, studies with L. donovaniinfected IL-4 Ϫ/Ϫ BALB/c mice indicate a less well appreciated effect for IL-4 in supporting Th1-type responses and limiting initial liver parasite replication (1,22,25). In addition, susceptibility to L. donovani is further enhanced in IL-4 receptor ␣-deficient (IL-4R␣ Ϫ/Ϫ ) BALB/c mice, in which higher liver parasite burdens correlated with deficient IFN-␥ secretion and impaired granuloma maturation. Since IL-13 also signals via IL-4 receptor ␣, a separate, similarly early-acting antileishmanial role was inferred for IL-13 (25).To formally test the role of IL-13 alone, IL-13 gene-disrupted mice on a BALB/c background (5) were infected intravenously with 1.5 ϫ 10 7 hamster spleen-derived L. donovani amastigotes (1 Sudan strain) (19). However, the course of infection in the liver, measured microscopically with tissue imprints and expressed as Leishman Donovan units (LDU) (19), proved nearly indistinguishable from the course of liver infection for WT BALB/c animals ( Fig. 1). In particular, the level of infection was similar at week 4, the point at which liver parasite burdens in IL-4R␣ Ϫ/Ϫ mice exceeded those in WT controls, before both groups resolved infection at week 8 (25).Nevertheless, IL-13 Ϫ/Ϫ mice showed defects in two linked expressions of Th1-cell-associated defense against L. donovani, IFN-␥ secretion and granuloma assembly (15, 16). IFN-␥ was ...