Since the isolation of the cDNA of macrophage migration inhibitory factor (MIF), a number of novel biological properties of this cytokine have been discovered. The primary amino acid sequence of MIF is well conserved among a wide range of species. MIF is constitutively expressed not only in T cells, but also in a variety of other cells, including macrophages and epithelial cells of various organs. With regard to its biological function, MIF plays an important role as a proinflammatory cytokine, initiating production of other inflammatory cytokines, and as an anterior pituitary-derived hormone, potentiating lethal endotoxemia. In particular, it should be emphasized that this protein has the potential to override the glucocorticoid-mediated suppression of inflammatory and immune responses. Judging from an array ofin vivostudies, it is clear that anti-MIF antibodies efficiently suppress endotoxin-and exotoxin-induced inflammation and immune responses as well as tumor growth and angiogenesis. This review presents the latest findings on the roles of MIF in inflammatory and immune responses, as well as in cell growth and differentiation.

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Signals transmitted by class II MHC molecules are important regarding cell function related to antigen presentation. Cross-linking HLA-DR molecules on B cells led to an increased production of IgM, with an enhanced expression of both membrane-and secretory-type IgM heavy chain mRNA. Increased IgM production was also observed in TCR-peptide-HLA-DR interaction, without the involvement of CD40-CD154 interaction. This event was inhibited specifically by piceatannol but not by PP 2, and ligation of HLA-DR on B cells enhanced Syk activity. Thus, HLA-DR molecules on B cells not only present antigenic peptides to T cells, but also upregulate IgM production, in association with Syk activation. We next found that peptide-pulsed monocytes preferentially produce proinflammatory monokines, by interacting with emetine-treated and DR-restricted T cells, whereas both DQ-restricted and DP-restricted T cells stimulated relatively higher levels of antiinflammatory monokine IL-10. Moreover, activation patterns of MAP kinases by anti-DR, anti-DQ and anti-DP Abs were distinct, which was further evidenced by the effect of MAP kinase inhibitors. HLA-DR, -DQ and -DP molecules may transmit distinct signals into monocytes through distinct MAP kinases and are functionally heterogeneous, which provide a clue to the need for generation of a multigene family of class II MHC.

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A germline IgVκ gene, A 30 is preferentially used for antibodies against selfantigens including DNA. A 30 may thus be autoantibody associated IgVκ gene. The A 30 gene is receptor edited in circulating B lymphocytes from normal individuals. SLE B lymphocytes failed to edit the A 30 gene, leading to the production of anti DNA autoantibody. Recombination activating gene (RAG) expression is essential for the receptor editing. Thus, expression of RAG proteins by peripheral blood mature B lymphocytes of normal subjects and patients with SLE has been analyzed. Normal B cells did not express RAG proteins spontaneously, and after activation withStaphylococcus aureusand IL-2, the B cells expressed RAGs. Recombination signal sequence (RSS) binding activity was verified by a gel shift assay in the nuclear proteins of activated B cells. Usage of a most downstream Jκ, Jκ 5, was evident in activated B cells expressing RAGs. λ chain and intracellular RAGs were simultaneously expressed on the purified κ + B cells after activation. Both findings suggest secondary light chain rearrangement in mature B cells. Some of RAG-expressing B cells could have failed in productive secondary rearrangement and they died via apoptosis. Thus, RAG expressing B cells would revise their surface Ig or would die, leading to elimination of the autoreactive B cells.
We found that anti-DNA autoantibody secreting B cells in patients with SLE did not express RAG spontaneously nor even after activation. Thus anti-DNA secreting B cells did not revise their Ig gene nor die via apoptosis, causing them to develop and persist autoantibody secretion by SLE B cells. These results suggest that failure of RAG reexpression in anti-DNA secreting B cells may be important for autoantibody production of SLE patients.

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T cells are well known to play an important role in the pathogenesis of systemic lupus erythematodes (SLE) . It has been reported that T cells from SLE patients show impaired responses to stimuli through T cell receptor (TCR) . TCR zeta chain is well recognized as an important molecule of the signal transduction through TCR. We have reported that significant part of SLE patients show diminished expression of TCR zeta chain that, in turn, may cause the defective responses of T cells often observed in SLE. Moreover, many investigators have demonstrated that SLE T cells show alternative profiles of cytokine production, such as Th 1 or Th 2 cytokines. It is possibly that diminished expression of TCR zeta chain in SLE T cells affects the production of cytokines. It has also demonstrated that TCR zeta chain knock out cell lines were established with Molt-4 cells. By using these cells, the function of SLE T cells with lower expression of TCR zeta chain changed from normal T cells, such as IL-2 production and proliferation. It is suggested that diminished expression of TCR zeta is responsible for alteration of cytokine productiom.

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Eosinophils and fibroblasts are believed to play important roles in the pathogenesis of bronchial asthma. This article focuses on the interaction between eosinophils and fibroblasts. Human eosinophil degranulation in the presence of lung fibroblasts is enhanced when both eosinophils and fibroblasts are activated by C5 a and TNF, respectively. This enhancement of eosinophil degranulation is partly dependent on GM-CSF from fibroblasts and on the adhesion of eosinophils to fibroblasts mediated by the ICAM-1/CD 18 dependent and CD 29-dependent mechanism. CD 11 b expression on human eosinophils increases after coculture with IL-1 β-stimulated fibroblasts, and this increase in CD 11 b expression is mediated by GM-CSF from fibroblasts and direct cell contact, similarly to above degranulation findings. On the other hand, IL-4 enhances SCF production by human lung fibroblasts, and IL-5-activated human eosinophils further augments SCF production stimulated by IL-4. Furthermore, eosinophil major basic protein interacts in a synergistic fashion with IL-1 a or TGF-β to further augment lung fibroblast IL-6-type cytokine production. It is possible that activated fibroblasts lead to the enhancement of eosinophil granule protein release and cytokine production, which results in the further activation of fibroblasts, leading to chronic asthmatic inflammation.

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Prostaglandin E synthase (PGES) catalyzes isomerization of PGH₂to PGE₂which exhibits potent and various biological activities. Here we report the molecular identification of two distinct glutathione-dependent PGESs, the terminal PGE₂-biosynthetic enzymes of the cyclooxygenase (COX) pathway. These PGESs exhibit unique functional coupling with two upstream COX isozymes, COX-1 and COX-2. Cytosolic PGES (cPGES), known as p 23, is constitutively and ubiquitously expressed and predominantly converts COX-1-derived PGH₂to PGE₂. Microsomal PGES (mPGES), identical to MGST 1-L 1, is an inducible perinuclear enzyme that is functionally linked with COX-2 in marked preference to COX-1. Increased supply of arachidonic acid by explosive activation of cytosolic phospholipase A₂allows COX-1 to be coupled with mPGES.

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We here investigated effects of intracellular Interleukin-1α (IL-1 α) produced in human gingival fibroblasts (HGF) on differentiation of osteoclasts (OCLs) precursor cells into OCLs and survival and fusion of mononuclear OCLs. Treatment with IL-1 β stimulated to produce intracellular IL-1 αin HGF. The cell layer of HGF treated with IL-1 β or not was subsequently fixed with 1 % paraformaldehyde. Cell membrane of the fixed HGF treated with IL-1 β possessed IL-1 activity, which was mainly attributed to IL-1 α. Soluble form of receptor activator of NF-κB ligand/ osteocalasts differentiation factor (RANKL/ODF) stimulated differentiation of RAW cells, a OCLs precursor cell line, into tartelet resistant acid phosphatase (TRAP) -positive OCLs. However, the RAW cells could not be differentiated into the TRAP-positive OCLs, when the cells were cultured on the fixed HGF treated with IL-1 β. On the other hand, the fixed HGF treated with IL-1 β stimulated survival and fusion of TRAP-positive mononuclear OCLs, when prefusion OCLs (pOCs), which were formed in coculture of murine osteoblasts and bone marrow cells, were cultured on the fixed HGF. The stimulatory effects of the fixed HGF treated with IL-1 β was suppressed by adding anti-human IL-1 α antibody or inhibition of cell-to-cell contact between the pOCs and the fixed HGF, but addition of anti-human M-CSF antibody and osteoprotegerin/osteoclastogenesis inhibitory factor (OPG/OCIF) had no effect. These results suggest that intracellular IL-1 α produced in HGF treated with IL-1 β has no effect on differentiation of OCLs precursor cells into OCLs, however it stimulates survival and fusion of mononuclear OCLs via cell-to-cell contact.

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We report a 68-year old woman with streptococcal toxic shock-like syndrome (TSLS), who survived after disarticulation of left arm and was analyzed for the focal and circulating levels of inflammatory cytokines. She was admitted because of narcotizing f asciitis of left forearm and a profound shock. We carried out disarticulation because erythematous rash of left arm progressively expanded to the trunk despite antimicrobial chemotherapy. After operation, she rapidly recovered from shock.Streptococcus pyogeneswas isolated from the exudates of the left forearm. We found increased levels of IL-8 and MCP-1 in sera, and also detected increased levels of IL-1β and TNF-α as well as these chamomiles in the exudate of the left forearm before disarticulation. After operation ohe circulating levels of IL-8 and MCP-1 rapidly decreased. A rapid growth of S. pyogenesand released streptococcal pyogenic exotoxin B strongly induce IL-8 and IL-1β production in the left forearm, and a massive release of neutrophil proteases might develop a fluminant fasciitis.

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