Rheumatoid arthritis (RA) is characterized by marked infiltration of the synovium by T cells. The mediator of joint inflammation has been shown to be both cellular and soluble mediated by multiple cytokines including chemokines. The concept of the crosstalking between adhesion molecules and cytokines and its relevance to inflammation is emerging.
Expression and function of adhesion molecules are tightly regulated via intracytoplasmic signaling induced by cytokine or chemokine stimulation, which process is designated“inside-out signal”. Such a regulation is most emphasized with inflammatory processes, in which T cells migrate from circulation into the tissue. T cell migration depends on integrin-mediated adhesion to endothelial ligands. Endothelial cells in RA synovium characteristically express heparan sulfate proteoglycan, which is involved in T cell integrin-triggering by“posting” chemokines, produced from synovial T cells, and by“relaying” them to their receptors on T cells which activate G-protein-dependent PI 3-kinase and actin-dependent integrin-triggering.
Adhesion molecules not only function as a glue but also transduce extracellular information into cytoplasmic organelle through“outside-in signal”, resulting in cell activation and cytokine production. For instance, the abundant ICAM-1 and CD 44 on RA synoviocytes not only potentially facilitate interaction to T cells or extracel-lular matrix but induce cytokine gene transcription in synoviocytes via nuclear factor activation.
Taken together, the busy two directional crosstalking among adhesion molecules and cytokines appears to be significant for the initiation and prolongation of inflammatory processes through T cell migration into RA synovial tissues and activation of both T cells and synovial cells there.

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Cosmetics and Quasi-drugs will play new important roles in the aging and stressful society. We have proposed 3 clinical approaches, i.e., anti drying, anti-UV radiation and antioxidation to prevent the skin disorders and aging. Especially, the importance of anti-oxidation is discussed in this paper. The results of the investigation of the peroxidation on the skin surface using a CL-HPLC system, it was considered that singlet oxygen was the key active oxygen species on a human skin. We have clarified the reaction rate constants of the skin surface lipids and thiotaurine with singlet oxygen. Thiotaurine is known as a compound in a metabolism of sulfur containing amino acids in a mammal. We propose that the reconstruction and the reinforcement of the anti-oxidation mechanism in the living system will be useful new clinical approaches in the skin.

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Activated neutrophils extracellularly release antibacterial defensins and cathelicidins from the granules. To elucidate the interactions between defensins and cathelicidins in the extracellular environment, we evaluated the individual and synergistic actions of defensins and cathelicidins in the presence of physiological concentration of NaCl (150 mM) . In the absence of NaCl, human defensin (HNP-1) and guinea pig defensins (GNCPs) exhibited the antibacterial activities against Escherichia coli and Staphylococcus aureus in a dose-dependent manner (0.1-10μg/ml) ; however, their activities were completely lost in the presence of 150 mM NaCl. In contrast, the antibacterial activities of human cathelicidin (CAP18/LL-37) and guinea pig cathelicidin (CAP11) were resistant to NaCI. Interestingly, HNP-1 and GNCPs synergized with CAP18/LL-37 and CAP11 to enhance the antibacterial activities against E. coli and S. aureus in the presence of 150 mM NaCl. Similarly, HNP-1 and GNCPs were synergistic with CAP18/LL-37 and CAP11 to potentiate the outer and inner membrane permeabilization of E. coli ML-35p. Together these observations likely indicate that when extracellularly released from neutrophils, defensins cannot function as antibacterial molecules by themselves, but can synergistically work with cathelicidins to exert the antibacterial activity in the extracellular milieu by potentiating the membrane permeabilization of target cells.

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We recently reported the occurrence of myelitis in adults with atopic dermatitis (AD) . In order to clarify the clinical features of myelitis with atopy, we retrospectively studied 68 consecutive patients with acute or subacute myelitis diagnosed in Kyushu University Hospital during the past 20 years. Of 40 patients with myelitis seen between 1994 and 1998, 19 (48%) had either AD or bronchial asthma (BA), while 2 of 28 (7%) myelitic patients treated between 1979 and 1993 did. Of the 40 patients with myelitis diagnosed between 1994 and 1998, 29 (73%) had hyperlgEaemia and 32 (80%) had mite antigen-specific IgE, while of 82 healthy controls and 43 patients with neurodegenerative disorders, 21% and 23% had hyperlgEaemia and 40% and 32% had mite antigen-specific IgE respectively. Seventeen myelitic patients with AD showed an involvement of primarily the posterior column of the spinal cord and paresthesia/dysesthesia in all four limbs, whereas 3 patients with BA, including 2 adults, showed most common involvement of the anterior horn cells with muscle weakness and atrophy following acute asthmatic attacks. In addition, 12 myelitic patients who had hyperlgEaemia and IgE antibodies to mite antigens but neither AD nor BA also showed partial involvement of the spinal cord. Among these myelitis patients with atopy, pleocytosis in the cerebrospinal fluid was rare, peripheral blood eosinophilia was frequent and corticosteroids were less beneficial. These findings suggest an emergence of myelitis associated with atopy in Japan.

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Lipopolysaccharide (LPS) tolerance, a hyporesponsive state to endotoxin or LPS stimulation, was induced in human monocytes by pretreatment of monocytes to a very low dose of Porphyromonas gingivalis LPS. Interleukin (IL) -6 production, but not IL-8 production, in response to LPS restimulation was significantly suppressed. The same pretreatment resulted in up regulation of superoxide (O₂) production. The selective induction of P. gingivalis LPS tolerance on IL-6 production developed in a time dependent manner during the primary culture without decrease of CD14 expression on cell surface. The expression of IL-6 mRNA decreased 10 h after restimulation of P. gingivalis LPS-pretreated monocytes. An up-regulation of IL 10 upon a second high dose LPS rechallenge occurred at the same time-point in the pretreated cells. Neutralization by an anti-IL-10 polyclonal antibody prevented IL-6 downregulation in P. gingivalis LPS-pretreated monocytes, whereas IL-8 production was not affected. These data suggest that tolerance of human monocytes to P. gingivalis LPS seems to be a state of differential deactivation in which some functions are impaired whereas others are retained or enhanced. Furthermore, autocrine IL-10 is essential for IL-6 downregulation in P. gingivalis LPS-tolerant monocytes.

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Neutrophil hyperfunction plays a critical role in the development and exacerbations of Behçet disease (BD) . However, precise mechanisms responsible for the neutrophil hyperfunction in this disease have been obscure. We here studied cytokine production by neutrophils in patients with BD. We found that freshly isolated neutrophils spontaneously expressed mRNA of interleukin (IL) -1α and tumor necrosis factor (TNF) -α, in patients with BD, irrespective of their disease activity. Neutrophils from normal donors never expressed the mRNA spontaneously. A gel shift assay demonstrated that spontaneous expression of an inducible transcription factor, NF-κB in nuclei of freshly isolated neutrophils from BD patients, but not from normal controls. The data suggest that constitutive NF-κB expression may be responsible for the spontaneous expression of IL-1α and TNF-α mRNA by the neutrophils. Furthermore, neutrophils also spontaneously produced Thl cell develop-ment-promoting cytokines, IL-12 and IL-18 in BD patients with active diseases. The culture supernatants containing IL-12 and IL-18 indeed enhanced interferon-γ production of T lymphocytes. Neutrophil hyperactivity may thus boost the pathogenic Thl immune responses of this disease, leading to the acute exacerbation of inflammation in patients with BD. Our present study emphasizes the importance of spontaneous cytokine production by the neutrophils in patients with BD.

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We reported here a case of Churg-Strauss syndrome whose diagnosis was given without the findings of systemic vasculitis and granulomatous angiitis. The patient was a 58 year-old female who has been followed at outpatient clinic in our hospital with the diagnosis of bronchial asthma. She admitted our hospital on May 27, 1999 with migrating polymyalgia, polyarthralgia and granulomatous skin lesions on her left forearm. In laboratory data, we found a significant eosinophilia in the peripheral blood, accelerated erythrocyte sedimentation rate, elevation of CRP, and so on. Pulmonary infiltrates were also found on the chest X-ray examination. However, any findings which suggested the presence of systemic vasculitis such as high fever were not found.
From her clinical course and laboratory findings, we gave her the diagnosis of Churg-Strauss syndrome based on the criteria for Churg-Strauss syndrome and the classification tree proposed by the American College of Rheumatology. Biopsy specimen from the skin lesion showed diffuse extravascular infiltration of eosinophils and neutrophils into dermis without the findings of granulomatous angiitis. She was successfully treated by corticosteroid, and discharged on August 20, 1999.

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