Chemotactic cytokines and inflammation. Biological properties of the lymphocyte and monocyte chemotactic factors ELCF, MCAF and IL-8.

This thesis discusses the phenotypic characteristics of different inflammatory dermatological diseases and sets this into context with the specific chemotactic ability of different cytokines. It further discusses the biological properties of different chemotactic cytokines and their relevance in certain inflammatory diseases. The term chemotaxis was introduced in 1884 by Pfeffer, who described it as directional migration of leukocytes along a gradient. Regular studies of chemotaxis were, however, not possible until 1962 when Boyden developed the chemotaxis chamber technique. This test has since then been improved, and it is now possible to define and characterize chemoattractants and examine the special chemotactic behavior of leukocytes. We investigated T lymphocyte responses towards different chemoattractants using a modified Boyden chamber technique and found that approximately 50% of normal individuals have cells which respond whereas T-cells from the remaining persons did not respond. We therefore chose human T lymphocytic cell lines as target cells for chemotaxis screening to avoid inter-individual variations among donors. T lymphocytic infiltrates dominated by CD4+, CD45R0+ memory T cells are characteristic for many dermatological inflammatory diseases. We have therefore performed experiments to evaluate whether an earlier described epidermal lymphocyte chemotactic factor (ELCF) from skin overlying a tuberculin skin reaction in addition with other cytokines specifically attracts different subsets of lymphocytes. ELCF which probably reflects a mixture of different epidermal T lymphocyte chemotactic factors rather than a single factor was shown to specifically attract CD4+, CD45R0+ T lymphocytes in contrast to fMLP, IL-8, C5a and LTB4, which induced equal chemotaxis for both CD4+ and CD8+ T lymphocytes. A newly described inhibitory cytokine IL-10 selectively attracted the CD8+ subpopulation of T lymphocytes, and it is suggested that IL-10 could be an important factor in the downregulation of an inflammatory response. The recently discovered neutrophil chemotactic and activating factor IL-8 has been shown to be chemotactic for T lymphocytes as well. It belongs to a family of 8,000-10,000 KDa peptides of which a monocyte chemotactic and activating factor MCAF is also a member. We showed that mRNA for IL-8 could be expressed in highly purified T lymphocytes only upon stimulation with ionomycin and PHA or PMA and PHA, and to a lesser extent PMA and IL-2. This is consistent with other reports of T lymphocytes requiring two signals for cytokine production. We showed that it was only the CD4+ subpopulation of the T lymphocytes that expressed IL-8 mRNA.(ABSTRACT TRUNCATED AT 400 WORDS)