Norio Naruse

Potentiation of enteral absorption of human interferon alpha and selective transfer into lymphatics in rats

Enhancement of human leucocyte interferon (HuIFN-α) absorption from rat large intestine was studied with the aid of lipid, surfactant and lipid-surfactant mixed micelles. Neither the emulsified lipid (linoleic acid) nor the surfactant (HCO60, polyoxyethylated [60 moles] hydrogenated castor oil) alone were able to enhance the absorption of HuIFN-α. However, linoleic acid-HCO60 mixed micelles enhanced the absorption of HuIFN-α from the large intestine. Highly selective delivery of HuIFN-α into the lymphatics compared to the blood was also observed.

Development of Interferon Suppositories. I. Enhanced Rectal Absorption of Human Fibroblast Interferon by Fusogenic Lipid via Lymphotropic Delivery in Rats

We attempted to enhance the rectal absorption of human fibroblast interferon (HuIFN-β) in rats by the administration of suppositories containing fusogenic lipid and a nontoxic surfactant. Suppositories containing either the lipid (linoleic acid) or the surfactant [HCO60; polyoxyethylated (60 mol) hydrogenated castor oil] alone failed to enhance the absorption of HuIFN-β. However, suppositories containing both linoleic acid and HCO60 facilitated the rectal absorption of HuIFN-β. The absorbed HuIFN-β was selectively delivered via the lymph.

Non-core Region Modulates Interleukin-11 Signaling Activity: GENERATION OF AGONIST AND ANTAGONIST VARIANTS*

Human interleukin-11 (hIL-11) is a pleiotropic cytokine administered to patients with low platelet counts. From a structural point of view hIL-11 belongs to the long-helix cytokine superfamily, which is characterized by a conserved core motif consisting of four α-helices. We have investigated the region of hIL-11 that does not belong to the α-helical bundle motif, and that for the purpose of brevity we have termed “non-core region.” The primary sequence of the interleukin was altered at various locations within the non-core region by introducing glycosylation sites. Functional consequences of these modifications were examined in cell-based as well as biophysical assays. Overall, the data indicated that the non-core region modulates the function of hIL-11 in two ways. First, the majority of muteins displayed enhanced cell-stimulatory properties (superagonist behavior) in a glycosylation-dependent manner, suggesting that the non-core region is biologically designed to limit the full potential of hIL-11. Second, specific modification of a predicted mini α-helix led to cytokine inactivation, demonstrating that this putative structural element belongs to site III engaging a second copy of cell-receptor gp130. These findings have unveiled new and unexpected elements modulating the biological activity of hIL-11, which may be exploited to develop more versatile medications based on this important cytokine.

A possible role of autogenous IFN-β for cytokine productions in human fibroblasts

It has been already known that human diploid fibroblasts are able to produce not only high levels of IFN‐β but also various kinds of cytokines by poly rI: poly rC, and some inflammatory cytokines are induced by IFN‐β gene activation. We also obtained similar results. However, in our system, cytokine productions were extremely enhanced by treating the cells with a low dose of type 1 IFN and the priming effects on cytokine productions were blocked by cycloheximide similar to those on IFN‐β productions. Most of cytokines were produced later than IFN‐β and synthesis patterns of their mRNA showed the same phenomena. We made clear that cytokine productions by poly rI: poly rC are mediated by secreted IFN‐β at a protein level using a monoclonal antibody against human IFN‐β. Further, it was shown that intra‐cellular IFN‐β which is not secreted might also participate in cytokine productions. Meanwhile, IL‐1β induced various kinds of cytokines in human fibroblasts and production time courses of these cytokines were similar to those of poly rI: poly rC induced cytokines. Although secreted IFN‐β was not detected in IL‐1β stimulated culture, expression of IFN‐β mRNA was augmented. These results showed that priming effects of type 1 IFN on cytokine productions by poly rI: poly rC might not be the direct action, but successive IFN‐β production might be essential in the production processes of other cytokines. Further, it was suggested that inducible IFN‐β might also take part in IL‐1β‐induced cytokine productions. J. Cell. Biochem. 100: 1459–1476, 2007.

Effect of Salicylate on the Uptake of Cefmetazole into Brain of Mice

Cefmetazole distribution into mice cerebral cortex was minimal when the drug was administered alone. However, the co-administration of salicylate or diethyl maleate enhanced cefmetazole uptake into the cerebral cortex, while it decreased the level of reduced nonprotein sulfhydryls in cerebral cortex. The enhanced cerebral uptake of cefmetazole was suppressed by the simultaneous administration of cysteamine with a concomitant recovery of the reduced nonprotein sulfhydryl concentration in cerebral cortex.