Defining the Involvement of p38α MAPK in the Production of Anti- and Proinflammatory Cytokines Using an SB 203580-resistant Form of the Kinase

Abstract

Despite its lack of specificity, the inhibitor SB 203580 has been widely used to implicate p38 mitogen-activated protein kinase (MAPK) in the synthesis of many cytokines. Here we show unequivocally that the production of interleukin (IL)-1␤, IL-6, IL-10, and tumor necrosis factor ␣ (TNF␣) requires p38 MAPK activity by demonstrating that the inhibitory effects of SB 203580 were reversed by expression of an SB 203580-resistant form of p38␣ (SBR-p38␣) that fails to bind to SB 203580. This strategy established the requirement for p38 activity for the lipopolysaccharide-stimulated production of IL-10, IL-1␤, and IL-6 by the monocytic cell WEHI 274 and the production of IL-6 and TNF␣ stimulated by ligation of the Fc-␥ receptor of the mast cell MC/9. Expression of SBR-p38␣ in primary macrophages abrogated the ability of SB 203580 to inhibit the lipopolysaccharide-stimulated production of TNF␣ but not of IL-10. Expression of SBR-p38␣ in primary T lymphocytes abrogated the ability of SB 203580 to inhibit the production of interferon-␥ induced by co-ligation of CD3 and CD28 but not the production of interferon-␥ or IL-10 induced by IL-12. These results suggest that the levels of p38 MAPK activity required for maximal cytokine production vary with different cytokines and stimuli.

Delayed Administration of Pyroglutamate Helix B Surface Peptide (pHBSP), a Novel Nonerythropoietic Analog of Erythropoietin, Attenuates Acute Kidney Injury

“…Activation of p38 MAPK occurs in response to ischemia in many organs and promotes cellular stress responses such as proliferation, differentiation and production of proinflammatory cytokines (66,67). IRI of the kidney results in the activation of p38 MAPK, whereas inhibition of the activity of this p38 MAPK in renal IRI attenuates dysfunction and injury (68).…”

Cyclooxygenase-2 Inhibitor SC-236 [4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-1-pyrazol-1-l] Benzenesulfonamide] Suppresses Nuclear Factor-κB Activation and Phosphorylation of p38 Mitogen-Activated Protein Kinase, Extracellular Signal-Regulated Kinase, and c-Jun N-Terminal Kinase in Human Mast Cell Line Cells

“…Several recent studies have reported that suppression of MAPKs in mast cells may be a useful tool to reduce mast cell number in the inflammatory response (Koranteng et al, 2004). It was reported that p38 MAPK inhibitor suppressed IL-6 and TNF-␣ production in monocytic or mast cells (Guo et al, 2003;Jeong et al, 2003), and inhibition of p38 MAPK and ERK also attenuated COX activity (Borsch-Haubold et al, 1998). In addition, P38, ERK, and JNK are known to participate in the pathway of iNOS expression (Wang et al, 2004).…”

A Nonerythropoietic Peptide that Mimics the 3D Structure of Erythropoietin Reduces Organ Injury/Dysfunction and Inflammation in Experimental Hemorrhagic Shock

“…Inhibition of eNOS activity also attenuates the cardioprotective effects of EPO (44). Recently, Su et al (45) have demonstrated that CD131, when activated by EPO, is able to activate Akt Activation of p38 MAPK promotes cellular stress responses such as proliferation, differentiation and production of proinflammatory cytokines and occurs in response to ischemia and hemorrhage in a number of organs (46,47). HR results in the activation of p38 MAPK (in male animals), while inhibition of the activity of this p38 MAPK in hemorrhagic shock attenuates renal, cardiac and lung injury (48)(49)(50).…”