To investigate the role of NF-IL6 in vivo, we have generated NF-IL6 (-/-) mice by gene targeting. NF-IL6 (-/-) mice were highly susceptible to infection by Listeria monocytogenes. Electron microscopic observation revealed the escape of a larger number of pathogens from the phagosome to the cytoplasm in activated macrophages from NF-IL6 (-/-) mice. Furthermore, the tumor cytotoxicity of macrophages from NF-IL6 (-/-) mice was severely impaired. However, cytokines involved in macrophage activation, such as TNF and IFN gamma, were induced normally in NF-IL6 (-/-) mice. Nitric oxide (NO) formation was induced to a similar extent in macrophages from both wild-type and NF-IL6 (-/-) mice. These results demonstrate the crucial role of NF-IL6 in macrophage bactericidal and tumoricidal activities as well as the existence of a NO-independent mechanism of these activities. We also demonstrate that NF-IL6 is essential for the induction of G-CSF in macrophages and fibroblasts.

Unrelated cord blood transplantation (CBT) has now become more common, but as yet there have been only a few reports on its outcome compared with bone marrow transplantation (BMT), especially for adults. We studied the clinical outcomes of 113 adult patients with hematologic malignancies who received unrelated BM transplants (n ‫؍‬ 45) or unrelated CB transplants (n ‫؍‬ 68). We analyzed the hematopoietic recovery, rates of graftversus-host disease (GVHD), risks of transplantation-related mortality (TRM) and relapse, and disease-free survival (DFS) using Cox proportional hazards models. The time from donor search to transplantation was significantly shorter among CB transplant recipients (median, 2 months) than BM transplant recipients (median, 11 months; P < .01). Multivariate analysis demonstrated slow neutrophil (P < .01) and platelet (P < .01) recoveries in CBT patients compared with BMT patients. Despite rapid tapering of immunosuppressants after transplantation and infrequent use of steroids to treat severe acute GVHD, there were no GVHD-related deaths among CB transplant recipients compared with 10 deaths of 24 among BM transplant recipients. Unrelated CBT showed better TRM and DFS results compared with BMT (P ‫؍‬ .02 and P < .01, respectively), despite the higher human leukocyte antigen mismatching rate and lower number of infused cells. These data strongly suggest that CBT could be safely and effectively used for adult patients with hematologic malignancies. (Blood. 2004;104:3813-3820)

Prostaglandin (PG) D 2 is the most abundant prostanoid produced in the central nervous system of mammals and has been implicated in the modulation of neural functions such as sleep induction, nociception, regulation of body temperature, and odor responses. We generated geneknockout mice for lipocalin-type PGD 2 synthase (L-PGDS) and found that the intrathecal administration of PGE 2 , an endogenous pain-producing substance, failed to elicit allodynia (touch-evoked pain), which is one typical phenomenon of neuropathic pain, whereas it evoked thermal hyperalgesia, in L-PGDS؊͞؊ mice. We also found that the allodynic response induced by the ␥-aminobutyric acid (GABA) A receptor antagonist bicuculline was selectively abolished in the L-PGDS؊͞؊ mice, among excitatory and inhibitory agents that induced allodynia in wild-type mice. Interestingly, simultaneous injection of a femtogram amount of PGD 2 with PGE 2 or bicuculline induced allodynia in L-PGDS؊͞؊ mice to the same extent as in wild-type mice. The PGE 2 -or bicucullineevoked allodynia in wild-type and in PGD 2 -supplemented L-PGDS؊͞؊ mice was blocked by a PGD 2 receptor antagonist given in a femtogram amount. These results reveal that endogenous PGD 2 is essential for both PGE 2 -and bicucullineinduced allodynia.Prostaglandin (PG) D 2 is the major prostanoid produced in the central nervous system (CNS) of mammals (1, 2) and has been shown to be involved in a variety of central actions, e.g., it induces sleep, decreases body temperature, and modulates odor and pain responses (3-5). Among the three enzymes catalyzing the conversion of PGH 2 to PGD 2 (6, 7), lipocalintype PGD synthase (L-PGDS) is considered to be responsible for the biosynthesis of PGD 2 in the CNS. L-PGDS is present mainly in the leptomeninges, choroid plexus, and oligodendrocytes of the CNS (8, 9), and is secreted into the cerebrospinal fluid to become ␤-trace (10, 11), a major protein component of the cerebrospinal fluid (12-14). The receptor for PGD 2 , the D type of PG (DP) receptor (15, 16), also is localized in the leptomeninges of the brain (17, 18). Therefore, PGD 2 is assumed to be produced in the membranous tissues and oligodendrocytes of the CNS; to circulate through the cerebrospinal fluid in the ventricular system, subarachnoidal space, and extracellular space in the CNS; to interact with DP receptors in the meninges; and to act as a neurohormone or an informational substance for global regulation of various CNS functions (5).Prolonged tissue damage or injury often leads to chronic pain states such that noxious stimuli evoke hyperalgesia and innocuous tactile stimuli evoke pain (allodynia). In relation to clinically relevant hyperalgesic states, such as inflammation and neuropathic pain, there is considerable interest in the neurochemical mechanisms of hyperalgesia and allodynia (19-21). Since Vane (22) reported that aspirin-like drugs prevented the development of inflammation by blocking the synthesis of PGs, it has been widely accepted that PGs are involved in inflammation an...

Selectins recognize ligands containing carbohydrate chains such as sialyl Lewis x (sLe x ) that are mainly presented at the terminus of N-acetyl lactosamine repeats on core 2 O-glycans. Several glycosyltransferases act successively to extend the N-acetyl lactosamine repeats and to synthesize sLe x , and ␤-1,4-galactosyltransferase (␤4GalT) plays a key role in these processes. Recently isolated 6 ␤4GalT genes are candidates, but their individual roles, including those in selectin-ligand biosynthesis, remain to be elucidated. More than 80% of the core 2 O-glycans on the leukocyte membrane glycoproteins of ␤4GalT-I-deficient mice lacked galactose residues in ␤-1,4 linkage, and soluble P-selectin binding to neutrophils and monocytes of these mice was significantly reduced, indicating an impairment of selectin-ligand biosynthesis. ␤4GalT-I-deficient mice exhibited blood leukocytosis but normal lymphocyte homing to peripheral lymph nodes. Acute and chronic inflammatory responses, including the contact hypersensitivity (CHS) and delayed-type hypersensitivity (DTH) responses, were suppressed, and neutrophil infiltration into inflammatory sites was largely reduced in these mice. Our results demonstrate that ␤4GalT-I is a major galactosyltransferase responsible for selectin-ligand biosynthesis and that inflammatory responses of ␤4GalT-I-deficient mice are impaired because of the defect in selectin-ligand biosynthesis. (Blood. 2003;102: 1678-1685)