SUMMARY:To understand the role of the proinflammatory cytokine interleukin-1 (IL-1) in mycobacterial inflammation, IL-1 ␣/␤ double-knockout (KO) mice were produced. These mice were infected with either Mycobacterium tuberculosis H37Rv by the airborne route using an airborne infection apparatus, and their capacities to control mycobacterial growth, granuloma formation, cytokine, and nitric oxide (NO) production were examined. The IL-1 ␣/␤ mice developed significantly larger (p Ͻ 0.01) granulomatous, but not necrotic, lesions in their lungs than wild-type (WT) mice after infection with H37Rv. Inflammatory lesions, but not granulomas, were observed in spleen and liver tissues from both IL-1 ␣/␤ KO and wild-type mice. Granulomatous lesion development in IL-1 ␣/␤ KO mice was not significantly inhibited by treatment with exogenous recombinant IL-1␣/␤. Compared with wild-type mice, splenic IFN-␥ and IL-12 levels were within the normal range. NO production by cultured alveolar macrophages from IL-1 ␣/␤ KO mice was lower than in wild-type mice but were increased by the addition of recombinant IL-1 ␣/␤. Our data clearly indicate that IL-1 is important for the generation of early-phase protective immunity against mycobacterial infection. (Lab Invest 2000, 80:759-767).

P-glycoprotein (MDR-1) is a well-known transporter that mediates eff lux of chemotherapeutic agents from the intracellular milieu and thereby contributes to drug resistance. MDR-1 also is expressed by nonmalignant cells, including leukocytes, but physiologic functions for MDR-1 are poorly defined. Using an initial screening assay that included >100 mAbs, we observed that neutralizing mAbs MRK16, UIC2, and 4E3 against MDR-1 specifically and potently blocked basal-to-apical transendothelial migration of mononuclear phagocytes, a process that may mimic their migration into lymphatic vessels. Antagonists of MDR-1 then were used in a model of authentic lymphatic clearance. In this model, antigen-presenting dendritic cells (DC) migrate out of explants of cultured human skin and into the culture medium via dermal lymphatic vessels. DC and T cells derived from skin expressed MDR-1 on their surfaces. Addition of anti-MDR-1 mAbs MRK16, UIC2, or the MDR-1 antagonist verapamil to skin explants at the onset of culture inhibited the appearance of DC, and accompanying T cells, in the culture medium by approximately 70%. Isotype-matched control mAbs against other DC molecules including CD18, CD31, and major histocompatibility complex I did not block. In the presence of MDR-1 antagonists, epidermal DC were retained in the epidermis, in contrast to control conditions. In summary, this work identifies a physiologic function for MDR-1 during the mobilization of DC and begins to elucidate how these critical antigen-presenting cells migrate from the periphery to lymph nodes to initiate T lymphocyte-mediated immunity.

The effects of nanoparticles toward on the male reproductive system of mice were investigated. Three sizes (14, 56 and 95 nm) of carbon black nanoparticles were intratracheally administered (0.1 mg/mouse for 10 times every week) to ICR male mice to investigate their adverse effects on the reproductive function. The serum testosterone levels were elevated significantly in the 14- and 56-nm carbon nanoparticles-exposed groups. Histological examination showed partial vacuolation of the seminiferous tubules. In addition, the effects of particle number towards the male reproductive system were investigated. The particle number controlled 14-nm nanoparticles-exposed group (14 N group, which has approximately the same particle number per unit volume as the 56-nm nanoparticles) showed fewer effects than did the 56-nm nanoparticles-exposed groups. These results suggest that carbon nanoparticle-exposure has adverse effects on the mouse male reproductive function. Furthermore, the effects of nanoparticles on the male reproductive system depend on particle mass rather than particle number.

Abstract:To investigate the role of TLR in the development of murine tuberculosis in vivo, TLR2 and TLR6 knockout (KO) mice were infected with Mycobacterium tuberculosis by placing them in the exposure chamber of an airborne infection apparatus. Both TLR2 and TLR6 KO mice survived until sacrifice at 12 weeks after infection. Infected TLR2 KO mice developed granulomatous pulmonary lesions with neutrophil infiltration, which were slightly larger in size than those in wild-type mice. Pulmonary levels of the mRNAs for inducible nitric oxide synthase (iNOS), TNF-␣, TGF-␤, IL-1␤, and IL-2 were significantly lower, but levels of the mRNAs for IL-4 and IL-6 were higher, than in wild-type (WT) mice. No significant difference was recognized in cytokine mRNA expression between TLR2 KO and WT mice at 12 weeks after infection. DNA binding by NF-B was low in TLR2 KO mice. On the other hand, TLR6 KO mice were not different from WT mice in terms of pulmonary histopathology, mRNA expression and CFU assay. Therefore, TLR2 does not play an essential role in the pathogenesis of murine tuberculosis, although it is important for defense against mycobacterial infection.

Several recent reports have suggested that sperm count and quality in normal men are declining. Various environmental chemical compounds may affect the male reproductive system. We propose here that diesel exhaust is an environmental pollutant with the potential to influence male reproductive function. Ultrastructural changes were observed in Leydig cells of mice exposed to diesel exhaust (0.3 mg diesel exhaust particles (DEP)/m3 through the airway, 12 h daily, up to 6 months) and reduction in LH receptor mRNA expression in Leydig cells was observed at a concentration of 1 mg DEP/m3. Daily sperm production per gram of testis dose-dependently decreased with exposure to DE for 6 months; 29%, 36%, and 53% reductions were observed at 0.3, 1.0, and 3.0 mg DEP/m3, respectively. A no-observed-adverse-effect level (NOAEL) was observed with approximately 30 micrograms DEP/m3, which is lower than the WHO-recommended limit.