C5a receptor and interleukin-6 are expressed in tissue macrophages and stimulated keratinocytes but not in pulmonary and intestinal epithelial cells

The anaphylatoxin derived from the fifth component of the human complement system (C5a) mediates its effects by binding to a single high-affinity rece ptor (C5aR/CD88), the expression of which has been traditionally thought to be restricted to granulocytes, monocytes, macrophages (M phi), and cell li nes of myeloid origin. Recent immunohistochemical data suggested that human bronchial and alveolar cells express C5aR as well. To reexamine the tissue distribution of human C5aR expression, transcription of the C5aR gene was investigated in normal and pathologically affected human lung (brronchopneu monia, tuberculosis), large intestine (acute appendicitis, Crohn's disease) , and skin (pyogenic granuloma, Lichen planus) using in situ hybridization, In contrast to previous evidence, C5aR mRNA could not be detected in pulmo nary or intestinal epithelial cells, whereas keratinocytes in inflamed but not in normal skin revealed detectable levels of C5aR transcripts. Addition ally, it could be documented that only migrating M phi express C5aR mRNA, w hereas sessile M phi in normal tissues and epithelioid/multinucleated M phi found in granulomatous lesions do not. Because C5a has been demonstrated t o upregulate the expression of interleukin (IL)-6 in human monocytes, we al so studied IL-6 gene transcription in parallel to the C5aR. IL-6 mRNA was d etectable in many tissue M phi. Surprisingly, a tight co-expression of C5aR and IL-6 mRNA was observed in keratinocytes from lesions of pyogenic granu loma and lichen planus, These results point to an as yet unknown role for C 5a in the pathogenesis of skin disorders beyond its well-defined function a s a chemoattractant and activator of leukocytes.