Cellular functions are mainly regulated by cognate interaction through adhesion molecules as well as soluble factors such as cytokines. The concept of the crosstalking between adhesion molecules and cytokines and its relevance to inflammation are emerging. Recently, various adhesion molecules have been identified and are known to involve in signaling in the two reverse direction.
First, expression and function of adhesion molecules are tightly regulated through 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 leukocytes migrate from circulation into inflamed tissue, leading to their accumulation there. Leukocyte migration depends on leukocyte integrin-mediated adhesion to endothelial ligands. ICAM-1 and VCAM-1, integrin-ligands, normally exhibit a restricted tissue distribution and their expression is induced by inflammatory cytokines such as IL-1β on a variety of cell types, especially on endothelial cells, at inflamed lesions. Contrarily, since integrins do not bind well until functionally activated, integrin requires triggering signals. The adhesive function of integrins is rapidly induced by chemokines mainly through G-protein-dependent PI 3-kinase and subsequent cytoskeletal actin-mediated conformational change and/or multimerization of integrins.
Second, 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. Immune cells and resident cells such as rheumatoid synoviocytes in inflamed tissue are highly activated and thereby efficiently function immune responses and produce various inflammatory mediators including cytokines and chemokines. When T cells are activated by antigen-presenting cells, both antigen-signal through T cell receptor and costimulatory signal via the binding of integrins and the other adhesion molecules such as CD28 are essential to complete T cell activation and cytokine production. Contrarily, the abundant ICAM-1 and CD44 on rheumatoid synoviocytes not only potentially facilitate interaction to T cells or extracellular matrix but induce cytokine gene transcription in synoviocytes via nuclear factor AP-1 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 immune cell migration into inflamed tissues and activation of both immune cells and resident cells there.

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We reported the abnormalities in bone marrow of rheumatoid arthritis (RA) patients. Lymphocytes and myeloid lineage cells increased in hematopoietic bone marrow of RA patients. The objective of this study is to investigate the bone marrow stromal cells established from RA patients and the role of stromal cells in joint destruction in RA. In the present study, we established nurse-like stromal cell (RA-BMNC) lines from bone marrow of RA patients. They were defined as nurse cells because of pseudoemperipolesis activity that allowed lymphocytes to migrate under-neath. The RA-BMNCs were observed to have many characteristics similar to that of nurse like stromal cells established from synovial tissues of patients with RA. RA-BMNC produced multiple inflammatory cytokines and hyaluronan (HA) . RA-BMNC produced significantly higher levels of IL-6, -8, and GM-CSF when coculture with lymphocytes. The cells also produced IL-1β, G-CSF and TNFα only when cocultured with lymphocytes. HA production by RA-BMNC was correlated with pseudoemperipolesis activity. RA-BMNC also plays an important role in the differentiation of myeloid lineage cells. These results indicate that RA-BMNC may play a pivotal role in the joint destruction of RA.

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The transcription factor NF-κB plays an important role in the induction of proinflammatory factors. NF-κB is sequestered in the cytoplasm by its inhibitory protein, IκB. Agents that stimulate NF-κB activation induce the phosphorylation of IκB by two IκB kinase (IKK) subunits, IKKα and IKKβ. The phosphorylation targets it for rapid degradation through ubiquitin-proteasome pathway, thereby releasing NF-κB to enter the nucleus. Several mitogen-activated protein kinase kinase kinases (MAP3Ks) play critical roles in NF-κB activation mediated through IKK pathway. We have found that TGFβ activated kinase 1 (TAK1), a member of the MAP3K family, stimulates NF-κB activation. TAK1 interacts with and activates IKKα and IKKβ. Furthermore, TNFα, but not TGFβ, activates TAK1 and the kinase negative TAK1 acts as a dominant negative inhibitor against TNFα-induced NF-κB activation. These results demonstrated a novel signaling pathway to NF-κB activation through TAK1, in which TAK1 may act as a regulatory kinase of IKKs.

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Since reactive oxygen intermediates are involved in the producing pathway of cytokines, NAC and glutathione (GSH), anti-oxidants, may inhibit the production of cytokines. We examined the TNFα production from rat alveolar macrophages stimulated by LPS and the effect of NAC and GSH on TNFα production. Alveolar macrophages in BAL fluid were separated from male SD rats and were stimulated with LPS at the concentration of 0.1 to 10μg/ml for 6 to 48 hours under the condition of 5% CO₂ at 37°C. TNFα concentration in the culture medium was measured using a mouse TNFα ELISA kit, which crossreacts with rat TNFα. LPS increased TNFα production from alveolar macrophages in dose-and time-dependent manners. NAC (5 mM to 30 mM) and GSH (10 mM to 30 mM) significantly inhibited the TNFα production induced by LPS. These findings suggest that reactive oxygen intermediates play an important role in the LPS-induced signal transduction pathway of cytokine production. NAC is considered to be useful as an anti-inflammatory drug.

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It is thought that prominent production of inflammatory cytokines and expression of adhesion molecules on the endothelial cells activated by unkown pathogens induce the formation of the vasculitis in Kawasaki disease (KD) . To study the anti-inflammatory effect of salicylazosulfapyridine (SASP) on the cardiovasculitis of KD, we examined the effect of SASP on IL-6 production by human coronary artery endothelial cells (HCAEC) . We used HCAEC because IL-6 production by HCAEC was greater than by human umbilical vein endothelial cells. SASP at less than 0.5 mM suppressed IL-6 production by LPS-induced HCAEC, and higher concentrations of SASP affected cell viability. On the other hand, SASP did not suppress IL-6 production by the cells stimulated with cytokines such as TNFα, IL-1 β and IL-4. Sulfapyridine and 5-aminosalicylic acid, which are degradation products of SASP, did not suppress IL-6 production.
These results show that SASP may have a direct inhibitoy effect on HCAEC activated by external substances such as LPS, which may be an effective agent in the cardiovasculitis of KD.

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