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(Circulation Research. 2002;91:681.)
© 2002 American Heart Association, Inc.

Molecular Medicine

Cooperation Between Secretory Phospholipase A₂ and TNF-Receptor Superfamily Signaling

Implications for the Inflammatory Response in Atherogenesis

Lucía Fuentes, Marita Hernández, Francisco Jesús Fernández-Avilés, Mariano Sánchez Crespo, María Luisa Nieto

From the Instituto de Biología y Genética Molecular (L.F., M.H., M.S.C., M.L.N.), Consejo Superior de Investigaciones Científicas, Facultad de Medicina, and Instituto de Ciencias del Corazón (F.J.F.-A.), Hospital Clínico Universitario, Valladolid, Spain.

Correspondence to Dr M. Sánchez Crespo, Instituto de Biología y Genética Molecular, Facultad de Medicina, 47005-Valladolid, Spain. E-mail mscres{at}ibgm.uva.es

Atherogenesis is the consequence of a variety of effector mechanisms rather than the result of a single functional molecule. In this connection, type IIA secretory phospholipase A₂ (sPLA₂) is an acute-phase reactant, which accumulates in atherosclerotic arterial walls, elicits several effects on monocytes, and has been related to the development of atherosclerosis. CD40/CD40 ligand pair is also a strong proatherogenic system. sPLA₂ produced an increase of the surface expression of CD40 in THP-1 monocytes and enhanced the effect of CD40 ligation on the expression of both Fas and FasL, thus indicating the existence of a positive cooperation between sPLA₂ and different elements of the TNF-receptor superfamily. Activation of the CD40/CD40L dyad with anti-CD40 antibody produced a small release of arachidonic acid and lacked any significant effect on the induction of cyclooxygenase-2, whereas the secretion of the chemokine MCP-1 and the surface display of CD11b, the chain of the integrin Mac-1, were upregulated. Engagement of CD40 did not influence the survival of THP-1 monocytes, but coincubation of THP-1 monocytes pretreated with anti-CD40 antibody and Jurkat cells induced a significant increase of the number of Jurkat cells showing binding of annexin-V, and nuclear condensation and fragmentation, thus indicating that this treatment might trigger a juxtacrine/paracrine mechanism of apoptotic death in sensitive cell types. This data indicates the existence of overlapping routes for the response to CD40, TNF-, and sPLA₂, thus allowing the development of distinct patterns of response in monocytic cells.

Key Words: apoptosis • atherosclerosis • cytokines • inflammation • lipid mediators

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