title: Combinatorial signals by inflammatory cytokines and chemokines mediate leukocyte interactions with extracellular matrix.
abstract: 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)-alpha acts as an adhesion-strengthening and stop signal for T cells migrating toward stromal cell-derived factor-1alpha, while transforming growth factor-beta down-regulates TNF-alpha-induced matrix metalloproteinase-9 secretion by monocytes. These findings indicate the importance of how one cytokine, such as TNF-alpha, 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.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: G G
authors.initials: GG
authors.lastname: Vaday
authors.forename: S
authors.initials: S
authors.lastname: Franitza
authors.forename: H
authors.initials: H
authors.lastname: Schor
authors.forename: I
authors.initials: I
authors.lastname: Hecht
authors.forename: A
authors.initials: A
authors.lastname: Brill
authors.forename: L
authors.initials: L
authors.lastname: Cahalon
authors.forename: R
authors.initials: R
authors.lastname: Hershkoviz
authors.forename: O
authors.initials: O
authors.lastname: Lider
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000494:pharmacology; D054377:Chemokine CXCL12; D018925:Chemokines / Q000494:pharmacology / Q000502:physiology*; D019743:Chemokines, CXC / Q000494:pharmacology; D002630:Chemotactic Factors / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D004357:Drug Synergism; D005109:Extracellular Matrix / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D007797:Laminin / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018715:Microscopy, Video; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C515255:CXCL12 protein, human; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D054377:Chemokine CXCL12; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D016207:Cytokines; D005353:Fibronectins; D007378:Interleukins; D007797:Laminin; D019402:Macrophage Inflammatory Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020780:Matrix Metalloproteinase 9