Chemotaxis by polymorphonuclear leukocytes

The ability of a cell or organism to direct its movement along a chemical gradient has fascinated biologists for over 100 yr. This process of chemotaxis requires transformation of directional information from the environment into a series of cellular responses resulting in directional movement. Many lower organisms including bacteria, protozoa, and slime molds exhibit chemotaxis. This ability helps them find nutrients, avoid noxious stimuli and aggregate at critical times in their development. Reports on higher organisms indicate that primordial germ cells (32, 36), neurons (123), tumor cells (124), and fibroblasts (115) exhibit chemotaxis. However, the leukocytes are the only vertebrate cells in which this ability has been shown definitively. Studies have focused on the chemotaxis exhibited by the neutrophilic polymorphonuclear leukocytes (PMNs), whose chemotaxis presumably facilitates their accumulation at sites of injury or infection. Chemical gradients are important in morphogenesis (27, 31,40, 75 ,105 ,106 ,151 ,162 ,173) . A gradient can impart at least two types of information to a given cell, positional and vectorial. Positional information is derived from the mean concentration of a given substance present around the cell. Positional information from gradients of diffusible substances has been implicated in the organization of insect epidermis (90), regeneration in hydra (174), and limb morphogenesis (135, 148, 149). Vectorial information at the cellular level depends on a cell's ability to detect the direction of the chemical gradient and develop a polarity along this direction (31, 76, 90). Most ceils have a polarity which corresponds to the overall tissue architecture. Some polarities undoubtedly arise from localized stimuli to which cells respond. For example, local stimuli probably contribute to the differentiation of the luminal and basal sides of epithelial cells. We know macrophages can selectively ingest opsonized particles, leaving other unopsonized particles attached to their membrane (60). Motile cells, including slime molds (29) and fibroblasts (3), are described as extending exploratory filopodia which, upon attachment to a suitable stimuli, induce cytoplasmic flow and expand into pseudopods. Other polarizations, for example, the direction of hair growth or cell migration, may be due to gradients of fixed or diffusible agents (31, 90). If the steepness of the gradient required for cell detection in these cases is similar to that needed by leukocytes (discussed below), one would expect the size of the gradient fields to be relatively small, probably in the millimeter range. Since we do not know the chemical nature of the gradient in most developmental systems, it is difficult to study the mechanisms involved in the establishment of cell polarities. In the case of leukocyte chemotaxis, we know some of the chemical signals. Many factors have been shown to be chemotactic for polymorphonuclear leukocytes (118,163) including: (a) serum factors (85, 158,169,172), particularly a fragment of the fifth component of complement (22, 132, 137, 157); (b) bacterial metabolites (86, 152); (c) cell-derived materials from sensitized lymphocytes (159) and from PMNs (18, 30, 111, 181); and (d) denatured proteins (168). Recently, in an attempt to identify a chemotactic factor derived from bacteria, Schiffmann et al. examined the possibility that N-formylmethionyl peptides might be the chemotactic agents since bacteria initiate their protein synthesis with Nformylmethionine (127). They discovered that a number of N-formylmethionyl peptides are in fact chemotactically active, some at very low concentrations (10 -1~ M) (127, 134). It is not clear