The actin cytoskeleton: an essential component for enhanced TNFalpha production by adherent monocytes.
Monocyte adherence induces the formation of focal adhesions, the interaction sites of intracellular signaling molecules and cytoskeletal proteins such as actin. We previously demonstrated that adherence potentiates human monocyte LPS-induced TNFalpha production. Hence, we hypothesized that the actin cytoskeleton is integral to adherence-induced priming for enhanced LPS-induced TNFalpha production. In contrast to nonadherent cells, LPS induced significant transcription of TNFalpha mRNA and production of TNFalpha in adherent monocytes. Disrupting the actin cytoskeleton with cytochalasin D (CD) in adherent monocytes inhibited LPS-induced TNFalpha production by 55%, thereby abrogating adherence-induced priming. Moreover, CD pretreatment abrogated adherence-induced activation of Pyk2, a major focal adhesion kinase, and ERK 1/2, a component of the mitogen-activated protein kinase (MAPK) signaling pathway, and it completely inhibited LPS-induced ERK 1/2 activation. However, CD treatment of nonadherent monocytes failed to inhibit cytokine production. In conclusion, the actin cytoskeleton is integral in the reprogramming of the monocyte for enhanced cytokine production and in maintaining this "primed" state.
Rosengart
Matthew R
MR
Department of Surgery, University of Washington, Seattle 98104, USA.
Arbabi
Saman
S
Bauer
Gregory J
GJ
Garcia
Iris
I
Jelacic
Sandra
S
Maier
Ronald V
RV
D000199:Actins / Q000378:metabolism* / Q000648:ultrastructure; D002448:Cell Adhesion; D002478:Cells, Cultured; D015638:Cytochalasin D / Q000494:pharmacology; D003599:Cytoskeleton / Q000378:metabolism* / Q000648:ultrastructure; D051418:Focal Adhesion Kinase 2; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D000199:Actins; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D015638:Cytochalasin D; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases