An alternative pathway of B cell activation: stilbene disulfonates interact with a Cl- binding motif on AEn-related proteins to stimulate mitogenesis.
Stilbene disulfonates are known to competitively inhibit Cl-/HCO3- flux through Band 3-related anion exchange (AE) proteins. To study the role of AE in lymphocyte activation, stilbene disulfonates were added to cultures of rat splenocytes (SPL). Four different stilbene derivatives were tested and each directly stimulated mitogenic proliferative responses of SPL. The mitogenic activity of these analogs paralleled their known patterns of interaction with Band 3-related AE proteins, as measured by; (a) their effective mitogenic concentrations, (b) their rank order of mitogenic potency [DIDS greater than SITS greater than DNDS congruent to DAzDS], (c) their patterns of nonreversible binding to the mitogenic receptor [DIDS much greater than SITS, DNDS], and (d) the specific, noncompetitive inhibition of their activity by the antagonist niflumic acid. Stilbene disulfonates directly activated purified B cell populations but not isolated T cells and furthermore, acted in synergy with anti-IgM to stimulate proliferation of SPL. These findings show that stilbene disulfonates represent a novel class of mitogens that interact with AEn-related proteins to stimulate an alternative activation pathway in B cells. These studies also indicate that immunomodulating activities of nonsteroidal anti-inflammatory drugs such as niflumic acid may be mediated, in part, by their interactions with AEn-related proteins.
Deane
K H
KH
Department of Microbiology and Immunology, East Carolina University School of Medicine, Greenville, NC 27858-4354.
Mannie
M D
MD
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000502:physiology*; D027321:Anion Transport Proteins; D001402:B-Lymphocytes / Q000276:immunology*; D002254:Carbonates / Q000378:metabolism; D002352:Carrier Proteins / Q000502:physiology*; D002712:Chlorides / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects*; D009544:Niflumic Acid / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew
D001457:Anion Exchange Protein 1, Erythrocyte; D027321:Anion Transport Proteins; D002254:Carbonates; D002352:Carrier Proteins; D002712:Chlorides; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; D009544:Niflumic Acid; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid