炎症病態における接着分子と情報伝達

Abstract

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.