* Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel, and
Department of Internal Medicine, Meir Hospital, Kfar Saba, Israel
Correspondence: Ofer Lider, Ph.D., Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. E-mail: ofer.lider{at}weizmann.ac.il
On their extravasation from the vascular system into inflamed
tissues, leukocytes must maneuver through a complex insoluble network
of molecules termed the extracellular matrix (ECM). Leukocytes navigate
toward their target sites by adhering to ECM glycoproteins and
secreting degradative enzymes, while constantly orienting themselves in
response to specific signals in their surroundings. Cytokines and
chemokines are key biological mediators that provide such signals for
cell navigation. Although the individual effects of various cytokines
have been well characterized, it is becoming increasingly evident that
the mixture of cytokines encountered in the ECM provides important
combinatorial signals that influence cell behavior. Herein, we present
an overview of previous and ongoing studies that have examined how
leukocytes integrate signals from different combinations of cytokines
that they encounter either simultaneously or sequentially within the
ECM, to dynamically alter their navigational activities. For example,
we describe our findings that tumor necrosis factor (TNF)-
acts as
an adhesion-strengthening and stop signal for T cells migrating toward
stromal cell-derived factor-1, while transforming growth factor-ß
down-regulates TNF--induced matrix metalloproteinase-9 secretion by
monocytes. These findings indicate the importance of how one cytokine,
such as TNF-, can transmit diverse signals to different subsets of
leukocytes, depending on its combination with other cytokines, its
concentration, and its time and sequence of exposure. The combinatorial
effects of multiple cytokines thus affect leukocytes in a
step-by-step manner, whereby cells react to cytokine signals in their
immediate vicinity by altering their adhesiveness, directional
movement, and remodeling of the ECM.
Key Words: chemokines • cytokines • cytoskeleton • metalloproteinase • T lymphocytes
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