Combinatorial signals by inflammatory cytokines and chemokines mediate leukocyte interactions with extracellular matrix

On their extravasation from the vascular system into inflamed tissues, leuk ocytes must maneuver through a complex insoluble network of molecules terme d the extracellular matrix (ECM). Leukocytes navigate toward their target s ites by adhering to ECM glycoproteins and secreting degradative enzymes, wh ile constantly orienting themselves in response to specific signals in thei r surroundings. Cytokines and chemokines are key biological mediators that provide such signals for cell navigation, Although the individual effects o f various cytokines have been well characterized, it is becoming increasing ly evident that the mixture of cytokines encountered hi the ECM provides im portant combinatorial signals that influence cell behavior. Herein, we pres ent an overview of previous and ongoing studies that have examined how leuk ocytes integrate signals front different combinations of cytokines that the y encounter either simultaneously or sequentially within the ECM, to dynami cally alter their navigational activities. For example, we describe our fin dings that tumor necrosis factor (TNF)-alpha acts as an adhesion-strengthen ing and stop signal for T cells migrating toward stromal cell-derived facto r-1 alpha, while transforming growth factor-beta down-regulates TNF-alpha - induced matrix metalloproteinase-9 secretion by monocytes, These findings i ndicate the importance of how one cytokine, such as TNF-alpha, cau transmit diverse signals to different subsets of leukocytes, depending on its combi nation with other cytokines, its concentration, and its time and sequence o f exposure. The combinatorial effects of multiple cytokines thus affect leu kocytes in a step-by-step manner, whereby cells react to cytokine signals i n their immediate vicinity by altering their ac adhesiveness, directional m ovement, and remodeling of die ECM.